European Heart Journal – Cardiovascular Imaging (2015) 16, 23–28 doi:10.1093/ehjci/jeu174
Outcomes of everolimus-eluting stent incomplete stent apposition: a serial optical coherence tomography analysis Kunihiro Shimamura1, Takashi Kubo 1, Takashi Akasaka 1*, Ken Kozuma 2, Kazuo Kimura3, Masaki Kawamura4, Tetsuya Sumiyoshi 5, Yasushi Ino 1, Minoru Yoshiyama 6, Shinjo Sonoda 7, Keiichi Igarashi 8, Akiyoshi Miyazawa2, Hiroyasu Uzui 9, Yuji Sakanoue 10, Toshiro Shinke 11, Yoshihiro Morino12, Kengo Tanabe 13, Kazushige Kadota 14, and Takeshi Kimura15 1
Department of Cardiovascular Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-8510, Japan; 2Division of Cardiology, Teikyo University Hospital, Tokyo, Japan; Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan; 4Division of Cardiology, Yokkaichi Social Insurance Hospital, Yokkaichi, Japan; 5Department of Cardiology, Sakakibara Heart Institute, Tokyo, Japan; 6Division of Internal Medicine and Cardiology, Osaka City University Graduate School of Medicine, Osaka, Japan; 7Division of Cardiology, University of Occupational and Environmental Health Japan, Kitakyushu, Japan; 8Division of Cardiology, Hokkaido Social Insurance Hospital, Sapporo, Japan; 9Department of Cardiovascular Medicine, University of Fukui Hospital, Fukui, Japan; 10Division of Cardiology, Higashisumiyoshi Morimoto Hospital, Osaka, Japan; 11Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; 12Division of Cardiology, Tokai University Hospital, Kanagawa, Japan; 13Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan; 14Division of Cardiology, Kurashiki Central Hospital, Kurashiki, Japan; and 15Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan 3
Aim
The aim of the present study was to evaluate the natural course of acute incomplete stent apposition (ISA) after secondgeneration everolimus-eluting stent (EES) when compared with first-generation sirolimus-eluting stent (SES) by using optical coherence tomography (OCT). ..................................................................................................................................................................................... Methods From the OCT substudy of the RESET trial, we identified 77 patients (EES ¼ 38 and SES ¼ 39) who successfully underand results went serial OCT examination at post-stenting and 8 –12-month follow-up. The presence of ISA was assessed in the OCT images, and ISA distance was measured from the centre of the strut blooming to the adjacent lumen border. Incomplete stent apposition was observed in all EES and SES at post-stenting, and it was persistent in 26% of EES and 38% of SES at 8 –12-month follow-up. Maximum ISA distance was significantly decreased during the follow-up period in both EES (315 + 94 –110 + 165 mm, P , 0.001) and SES (308 + 119–143 + 195 mm, P , 0.001). Receiver-operating curve analysis identified that the best cut-off value of OCT-estimated ISA distance at post-stenting for predicting late-persistent ISA at 8–12-month follow-up in EES and SES was .355 and .285 mm, respectively. ..................................................................................................................................................................................... Conclusions The second-generation EES showed better healing of acute ISA in comparison with the first-generation SES. Optical coherence tomography can predict late-persistent ISA after DES implantation and provide useful information to optimize PCI.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Optical coherence tomography † Incomplete stent apposition † Drug-eluting stent
Introduction Acute incomplete stent apposition (ISA) can occur at the time of stent implantation. The mechanism underlying acute ISA seems to be related with a procedural technique, and additional balloon
angioplasty is often performed to improve ISA. The acute ISA might either resolve or persist at follow-up. A previous optical coherence tomography (OCT) study has demonstrated that the distance between the stent strut and vessel wall .260 mm immediately after an index procedure was the corresponding cut-off point for
* Corresponding author. Tel: +81 734410621; fax: +81 734460631. Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
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Received 14 February 2014; accepted after revision 10 August 2014; online publish-ahead-of-print 23 October 2014
24 predicting late-persistent ISA in the first-generation DES.1 However, the natural course of acute ISA after second-generation DES remains unknown. OCT is a high-resolution (10 –20 mm) intracoronary imaging modality, which enables detailed in vivo assessment of individual strut apposition.2 Basic and clinical studies have reported the high accuracy and excellent reproducibility of OCT for an identification of ISA.3 – 5 The aim of the present study was to evaluate the natural course of acute ISA after second-generation everolimus-eluting stent (EES) when compared with the first-generation sirolimus-eluting stent (SES) by using OCT.
Methods Study population and protocol
OCT image acquisition A time-domain OCT system (Model M2 Cardiology Imaging System, LightLab Imaging, Inc., St Jude Medical, St Paul, MN, USA) was used in the present study. Images were acquired as previously reported.5 Briefly, a 0.016-inch OCT catheter (ImageWire, LightLab Imaging, Inc., St Jude Medical, St Paul, MN, USA) was advanced to the distal end of the DES-treated lesion through a 3F occlusion balloon catheter (Helios, Goodman Co., Ltd., Nagoya, Japan). To remove the blood from the field of view, the occlusion balloon was inflated at 0.4 –0.6 atmosphere at the proximal site of the DES-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. For the assessment of the proximal coronary arteries, a continuous-flushing (non-occlusive) technique of OCT imaging was used. To flush the vessel, a mixture of commercially available dextran 40 and lactated Ringer’s solution (low-molecular-weight Dextran L Injection, Otsuka Pharmaceutical Factory, Tokushima, Japan) was infused directly from the guiding catheter at a rate of 2.5 – 4.5 mL/s with an injector pump. Regardless of the OCT imaging technique used, the entire DES-treated lesion was imaged with an automatic pullback device travelling at 1 mm/s in all cases. 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 undertaken in a core laboratory (Wakayama Medical University, Wakayama, Japan) by an independent analysts blinded to stent-type allocation and clinical and procedural characteristics of the patients, using a dedicated off-line review system with a semiautomated contour-detection software (LightLab Imaging, Inc., St Jude Medical, St Paul, MN, USA). After calibration adjustment, OCT images were assessed to identify the ISA at intervals of 1 mm in the DES-treated lesions. When a strut was clearly separated from vessel wall, ISA distance was measured from the centre of the strut blooming to the adjacent lumen border. An incompletely apposed strut was defined as a strut with ISA distance .100 mm in EES and .170 mm in SES. This criterion was determined by adding the actual strut thickness and polymer thickness to the OCT resolution limit. The target site for OCT analysis in the present study was the site with maximal ISA distance at post-stenting. Serial OCT images at post-stenting and 8 – 12-month follow-up were reviewed side by side on the screen, and the target site was matched based on the distance from landmarks such as branches, calcifications, or stent edges. Cross-sectional areas of stent, intra-stent lumen, intra-stent tissue (defined as stent minus intra-stent lumen), and ISA (defined as extra-stent lumen) were measured at the target site. Intra-stent thrombus was identified as a mass protruding beyond the stent strut into the lumen with significant attenuation behind the mass.7 Representative serial OCT images of EES and SES are shown in Figure 1.
Coronary angiography Angiograms at post-stenting and 8 – 12-month follow-up were evaluated at one angiographic core laboratory (Cardiocore, Tokyo, Japan) with the use of CAAS 5.9 (Pie Medical Imaging, Maastricht, The Netherlands). The reference lumen diameter, minimum lumen diameter, and per cent diameter stenosis [(1 2 minimum lumen diameter/reference lumen diameter) × 100] were calculated. In-stent binary restenosis was defined as a diameter stenosis .50% at follow-up angiography.
Clinical outcomes The incidence of death, myocardial infarction, TLR and stent thrombosis was evaluated 8 –12 months after PCI. TLR was defined as any re-intervention (surgical or percutaneous) to treat in-stent restenosis.
Statistical analysis Statistical analysis was performed using the IBM SPSS Statistics software version 20.0 (SPSS, Inc., Chicago, IL, USA). Categorical variables were presented as frequencies, with comparisons using x2 statistics. Continuous variables were presented as mean + standard deviation and were compared using paired Student’s t-test (comparison between EES vs. SES) or unpaired Student’s t-test (comparison between post-stenting vs. follow-up). A P – value ,0.05 was considered statistically significant. Receiver-operating characteristic (ROC) curve analysis was used to identify the best cut-off value of OCT-estimated ISA distance at post-stenting for predicting late-persistent ISA at 8 – 12-month follow-up. The best cut-off value was determined by the maximum sum of sensitivity and specificity.
Results Patient characteristics Patient clinical characteristics are summarized in Table 1. There were no significant differences between EES and SES in terms of age, gender, coronary risk factors, clinical presentation at index procedure, stented coronary arteries, stent profiles (numbers of stents
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The Randomized Evaluation of Sirolimus-eluting vs. Everolimus-eluting stent Trial (RESET) was a prospective multi-centre randomized openTM label trial comparing EES (Xience V , Abbot Vascular, Inc., Santa Clara, TM CA, USA) with SES (Cypher Select-Plus , Cordis/Johnson & Johnson, Miami Lakes, FL, USA) in terms of target lesion revascularization (TLR) (ClinicalTrials.gov identifier NCT01035450).6 Details of the study protocols have been reported.6 The present study is a pre-specified imaging substudy of the RESET. OCT sites (n ¼ 16 centres) were pre-selected based on their willingness to participate in the imaging substudy of RESET. The patients were not randomly selected, but were selected by the OCT site investigators. Of the 3197 patients enrolled in RESET, 77 patients (EES ¼ 38 and SES ¼ 39) underwent serial OCT examination at post-stenting with optimization by post-dilatation and 8 – 12-month follow-up. The decision to carry out post-dilatation was made by the operator based on the angiographic images. The exclusion criteria for OCT were as follows: (i) apparent congestive heart failure, (ii) renal insufficiency (serum creatinine .2.0 mg/dL), and (iii) lesions unsuitable for OCT imaging (left main coronary artery lesions, ostial right coronary artery lesions, excessively tortuous vessel, and vessel size .4.0 mm). The study was approved by the institutional review board or medical ethics committee at each participating centre, and all the patients gave written informed consent.
K. Shimamura et al.
25
Incomplete stent apposition in DES
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Figure 1: Representative OCT images of EES and SES. ISA at post-stenting (arrows) resolved at follow-up in EES [(A) maximum ISA distance ¼ 370– 0 mm; ISA area ¼ 0.71 –0 mm2; intra-stent lumen area ¼ 7.18 – 5.91 mm2] and SES [(B) maximum ISA distance ¼ 260 – 0 mm; ISA area ¼ 0.79– 0 mm2; intra-stent lumen area ¼ 4.40– 3.66 mm2].
per lesion, stent diameter, total stent length per lesion), and other procedural characteristics. The mean duration between the index procedure and follow-up in EES and SES was 9.7 + 1.6 and 9.9 + 1.9 months, respectively. The recommended antiplatelet regimen included aspirin (≥81 mg daily) indefinitely and thienopyridines (75 mg clopidogrel or 200 mg ticlopidine daily) for at least 3 months.
QCA measurements QCA measurements at post-stenting and 8 –12-month follow-up are summarized in Table 2. During the follow-up period, the per cent diameter stenosis in the stented segment increased from 8.2 + 7.4 to 12.7 + 9.5% in EES (P ¼ 0.023) and from 8.8 + 6.2 to 13.2 + 10.2% in SES (P ¼ 0.007). Two patients in EES and three patients in
SES had in-stent binary restenosis and required TLR. There were no stent thrombosis, myocardial infarction, and cardiovascular death during the follow-up period.
OCT findings OCT images at post-stenting and 8–12-month follow-up were available for all patients. OCT findings are summarized in Table 3. ISA was observed in all EES and SES at post-stenting, and it was persistent in 26% of EES and 38% of SES at follow-up. Maximum ISA distance significantly decreased during the follow-up period in both EES (315 + 94 –110 + 165 mm, P , 0.001) and SES (308 + 119– 143 + 195 mm, P , 0.001). An intra-stent tissue area at follow-up was significantly greater in EES compared with SES (0.97 + 0.53 vs. 0.73 + 0.37 mm2, P , 0.001). The results of ROC curve analysis
26
K. Shimamura et al.
for predicting late-persistent ISA are shown in Figure 2. The best cut-off value of OCT-estimated ISA distance at post-stenting for predicting late-persistent ISA at 8–12-month follow-up in EES and SES was .355 and .285 mm, respectively. Maximum ISA distance was not different between ACS and stable AP in both EES (post-stenting: 301 + 93 vs. 320 + 96 mm, P ¼ 0.630; and 8–12-month follow-up: 51 + 145 vs. 125 + 169 mm, P ¼ 0.263) and SES (post-stenting: 281 + 63 vs. 314 + 128 mm, P ¼ 0.517; and 8– 12-month follow-up: 151 + 148 vs. 141 + 206 mm, P ¼ 0.897).
Discussion The main findings of this study were the following: (i) ISA was persistent in 26% of EES and 38% of SES at 8 –12-month follow-up; and (ii) The best cut-off value of OCT-estimated ISA distance at poststenting for predicting late-persistent ISA at 8–12-month follow-up in EES and SES was .355 and .285 mm, respectively. OCT can predict late-persistent ISA after DES implantation and provide useful information to optimize PCI.
Acute ISA Table 1
Patient clinical characteristics EES (n 5 38)
SES (n 5 39)
P-value
................................................................................ 67.1 + 9.5
69.1 + 9.0
0.308
Male gender, n (%) Coronary risk factors, n (%)
30 (79)
30 (77)
0.831
Hypertension
34 (89)
33 (85)
0.526
Dyslipidaemia Diabetes mellitus
31 (82) 18 (47)
30 (77) 16 (41)
0.615 0.575
Current smoker
19 (50)
20 (51)
0.910
30 (79)
32 (82)
8 (21)
7 (18)
Clinical presentation, n (%) Stable AP ACS
0.731
Stented coronary arteries, n (%) LAD 14 (37) LCX RCA Stent and procedure
0.409 20 (51)
9 (24)
6 (16)
15 (39)
13 (33) 1.2 + 0.5
Resolution of acute ISA
No. of stent per lesion
1.2 + 0.6
Stent diameter, mm Total stent length per lesion, mm
3.1 + 0.4 3.0 + 0.3 0.392 26.7 + 14.4 27.2 + 14.2 0.886
Direct stenting, n (%) Post-dilatation, n (%)
12 (32) 24 (63)
10 (26) 32 (82)
0.564 0.063
Maximum inflation pressure, atm
15.3 + 4.0
16.7 + 3.7
0.120
0.961
Values are given as n (%) or mean + standard deviation. AP, angina pectoris; ACS, acute coronary syndrome; EES, everolimus-eluting stent; LAD, left anterior-descending coronary artery; LCX, left circumflex coronary artery; RCA, right coronary artery; SES, sirolimus-eluting stent.
Table 2
The process of the resolution of acute ISA is initiated by growth of endothelial cells, and subsequent neointimal proliferation fills in the space between the ISA struts and the vessel wall.8 However, this re-endothelialization process is limited in time: it stops after 2–6 weeks in the animal models.12 Because the re-endothelialization stops after weeks or months, the neointima could fail to cover stent struts if the ISA space is large. OCT allows us to evaluate neointimal proliferation after DES in the clinical setting. Recent OCT studies showed that EES had greater neointimal proliferation than SES (mean neointimal hyperplasia thickness at 9 months after stent implantation: 115 + 52 vs. 89 + 58 mm, P ¼ 0.001) while there was no significant difference in in-stent restenosis and TLR between the two stents.13 An OCT study by Kawamori et al. 1 reported that the best cut-off values of ISA distance at post-stenting for predicting late-persistent ISA at 8-month follow-up in the first-
QCA measurements at post-stenting and 8 –12-month follow-up EES (n 5 38)
............................................................
SES (n 5 39)
............................................................
Post-stenting
Follow-up
P-value
Post-stenting
Follow-up
P-value
2.88 + 0.56 2.64 + 0.55
2.87 + 0.53 2.50 + 0.49
0.933 0.026
2.83 + 0.46 2.58 + 0.42
2.78 + 0.47 2.40 + 0.46
0.260 ,0.001
8.2 + 7.4
12.7 + 9.5
0.023
8.8 + 6.2
13.2 + 10.2
0.007
............................................................................................................................................................................... Reference lumen diameter, mm Minimum lumen diameter, mm Diameter stenosis, %
Values are given as mean + SD. EES, everolimus-eluting stent; QCA, quantitative coronary angiography; SES, sirolimus-eluting stent.
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Age, years
Acute ISA is mostly technique dependent and can occur after implantation of any type of stent. Acute ISA can resolve or persist at follow-up. Persistent ISA after DES implantation is associated with lessneointimalhyperplasia and presumably reduced re-endothelialization in comparison with acute ISA that resolves spontaneously.8 – 11 An OCT study reported that 77% of acute ISA in the first-generation DES resolved at 8-month follow-up.1 Acute ISA which will resolve spontaneously could be left without additional procedures including high-pressure post-dilation with large-diameter balloon.1 Therefore, elucidation of the natural course of acute ISA is important regarding the safety and cost-effectiveness of PCI. The present study demonstrated that the stent struts with ISA distance ,355 mm immediately after second-generation EES implantation could resolve spontaneously. These data might help us avoid unnecessary additional procedures frequently performed after stent implantation to achieve stent optimization.
27
Incomplete stent apposition in DES
Table 3
OCT findings at post-stenting and 8 –12-month follow-up EES (n 5 38)
.............................................................. Post-stenting
SES (n 5 39)
.............................................................
Follow-up
P-value
Post-stenting
Follow-up
P-value
............................................................................................................................................................................... ISA, n (%)
38 (100)
10 (26)
,0.001
39 (100)
15 (38)
,0.001
Maximum ISA distance, mm
315 + 94
110 + 165
,0.001
308 + 119
143 + 195
,0.001
Stent area, mm2 Intra-stent lumen area, mm2
6.86 + 1.66 6.81 + 1.66
6.92 + 1.71 6.02 + 1.72
0.128 ,0.001
6.53 + 1.88 6.52 + 1.88
6.52 + 1.89 5.80 + 1.89
0.256 ,0.001
Intra-stent tissue area, mm2
0.08 + 0.12*
0.97 + 0.53*
,0.001
0.01 + 0.02
0.73 + 0.37
,0.001
ISA area, mm2
0.50 + 0.24*
0.17 + 0.27
,0.001
0.95 + 0.70
0.41 + 0.66
,0.001
Values are given as n (%) or mean + SD. EES, everolimus-eluting stent; ISA, incomplete stent apposition; OCT, optical coherence tomography; SES, sirolimus-eluting stent. *P , 0.05 vs. SES.
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Figure 2: Receiver-operating curve analysis for predicting late-persistent ISA. The best cut-off value of OCT-estimated ISA distance at poststenting for predicting late-persistent ISA at 8 – 12-month follow-up was .355 mm in EES [(A) sensitivity ¼ 100%; specificity ¼ 75%; positive predictive value ¼ 54%; negative predictive value ¼ 100%; area under the curve (AUC) ¼ 0.905] and .285 mm in SES [(B) sensitivity ¼ 93%; specificity ¼ 83%; positive predictive value ¼ 77%; negative predictive value ¼ 95%; AUC ¼ 0.947].
generation SES and paclitaxel-eluting stent were .280 and .260 mm, respectively. In the present study, we identified that the best cut-off value of OCT-estimated ISA distance at post-stenting for predicting late-persistent ISA in the second-generation EES was .355 mm. Acute ISA is easy to be resolved in the second-generation EES compared with the first-generation SES.
ISA and stent thrombosis The role of late ISA in the pathogenesis of late stent thrombosis remains controversial. A retrospective IVUS study by Cook et al. 14 demonstrated that the late-persistent or late-acquired ISA was more frequent (77 vs. 12%, P , 0.001) and the maximum ISA area was larger (8.3 + 7.5 vs. 4.0 + 3.8 mm2, P ¼ 0.03) in patients with
very late stent thrombosis compared with those without very late stent thrombosis after DES. Similarly, a case –control OCT study by Guagliumi et al. 15 showed that the frequency of late malapposed struts per patient was higher [4.60% (1.85–7.19%) vs. 1.81% (0.00– 2.99%), P , 0.001] and the maximum length of segments with malapposed struts was longer [1.40 mm (0.68–1.93 mm) vs. 0.00 mm (0.00–0.00 mm), P ¼ 0.001] in patients with late DES thrombosis compared with control subjects. We investigated late-persistent ISA by serial OCT examination at post-stenting and 8–12-month follow-up; however, the present study was not powered for evaluating stent thrombosis. Because the frequency of late and very late stent thrombosis is extremely low, a prospective study with a larger population and longer-time follow-up might be
28 needed to investigate the relationship between late ISA and stent thrombosis.
Limitations There are a number of limitations in the present study. First, although the intended OCT subsets represent the greater entire cohort of the RESET, they are derived only from centres specializing in OCT, and therefore are subject to some degree of selection bias. Second, we examined only EES and SES; therefore, our results cannot be applied to other DES. Third, the limited longitudinal resolution of OCT imaging may have biased the identification of corresponding images in serial (baseline and follow-up) OCT studies. Fourth, because we performed follow-up at only one point in time, further changes in the ISA are left to be clarified by the repeated follow-up studies. Fifth, the relationship between late-persistent ISA detected by OCT and the risk of adverse clinical events, stent thrombosis in particular, needs to be demonstrated in a prospective long-term study with a larger sample size. Finally, late-acquired ISA was beyond the scope of our study. Further studies are required to assess the frequency, mechanisms, and clinical implications of late-acquired ISA.
Conclusions
Acknowledgements We thank Yoichi Nozaki, MD, Hiroyuki Kyono, MD, Tsukasa Inada, MD, Mitsuru Abe, MD, Kazushi Urasawa, MD, and Yukio Ozaki, MD for OCT image collections. Conflict of interest: T.K., K.I., and K.K. were advisory board members of Abbott Vascular. The other authors do not have a conflict of interest in the context of the subject of this article.
Funding This study was funded by Abbott Vascular.
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Compared the first-generation with SES, the second-generation EES showed more favourable vascular response in the resolution of acute ISA. OCT can predict late-persistent ISA after DES implantation and provide useful information to optimize PCI.
K. Shimamura et al.
Outcomes of everolimus-eluting stent incomplete stent apposition: a serial optical coherence tomography analysis Kunihiro Shimamura1, Takashi Kubo 1, Takashi Akasaka 1*, Ken Kozuma 2, Kazuo Kimura3, Masaki Kawamura4, Tetsuya Sumiyoshi 5, Yasushi Ino 1, Minoru Yoshiyama 6, Shinjo Sonoda 7, Keiichi Igarashi 8, Akiyoshi Miyazawa2, Hiroyasu Uzui 9, Yuji Sakanoue 10, Toshiro Shinke 11, Yoshihiro Morino12, Kengo Tanabe 13, Kazushige Kadota 14, and Takeshi Kimura15 1
Department of Cardiovascular Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-8510, Japan; 2Division of Cardiology, Teikyo University Hospital, Tokyo, Japan; Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan; 4Division of Cardiology, Yokkaichi Social Insurance Hospital, Yokkaichi, Japan; 5Department of Cardiology, Sakakibara Heart Institute, Tokyo, Japan; 6Division of Internal Medicine and Cardiology, Osaka City University Graduate School of Medicine, Osaka, Japan; 7Division of Cardiology, University of Occupational and Environmental Health Japan, Kitakyushu, Japan; 8Division of Cardiology, Hokkaido Social Insurance Hospital, Sapporo, Japan; 9Department of Cardiovascular Medicine, University of Fukui Hospital, Fukui, Japan; 10Division of Cardiology, Higashisumiyoshi Morimoto Hospital, Osaka, Japan; 11Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; 12Division of Cardiology, Tokai University Hospital, Kanagawa, Japan; 13Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan; 14Division of Cardiology, Kurashiki Central Hospital, Kurashiki, Japan; and 15Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan 3
Aim
The aim of the present study was to evaluate the natural course of acute incomplete stent apposition (ISA) after secondgeneration everolimus-eluting stent (EES) when compared with first-generation sirolimus-eluting stent (SES) by using optical coherence tomography (OCT). ..................................................................................................................................................................................... Methods From the OCT substudy of the RESET trial, we identified 77 patients (EES ¼ 38 and SES ¼ 39) who successfully underand results went serial OCT examination at post-stenting and 8 –12-month follow-up. The presence of ISA was assessed in the OCT images, and ISA distance was measured from the centre of the strut blooming to the adjacent lumen border. Incomplete stent apposition was observed in all EES and SES at post-stenting, and it was persistent in 26% of EES and 38% of SES at 8 –12-month follow-up. Maximum ISA distance was significantly decreased during the follow-up period in both EES (315 + 94 –110 + 165 mm, P , 0.001) and SES (308 + 119–143 + 195 mm, P , 0.001). Receiver-operating curve analysis identified that the best cut-off value of OCT-estimated ISA distance at post-stenting for predicting late-persistent ISA at 8–12-month follow-up in EES and SES was .355 and .285 mm, respectively. ..................................................................................................................................................................................... Conclusions The second-generation EES showed better healing of acute ISA in comparison with the first-generation SES. Optical coherence tomography can predict late-persistent ISA after DES implantation and provide useful information to optimize PCI.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Optical coherence tomography † Incomplete stent apposition † Drug-eluting stent
Introduction Acute incomplete stent apposition (ISA) can occur at the time of stent implantation. The mechanism underlying acute ISA seems to be related with a procedural technique, and additional balloon
angioplasty is often performed to improve ISA. The acute ISA might either resolve or persist at follow-up. A previous optical coherence tomography (OCT) study has demonstrated that the distance between the stent strut and vessel wall .260 mm immediately after an index procedure was the corresponding cut-off point for
* Corresponding author. Tel: +81 734410621; fax: +81 734460631. Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
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Received 14 February 2014; accepted after revision 10 August 2014; online publish-ahead-of-print 23 October 2014
24 predicting late-persistent ISA in the first-generation DES.1 However, the natural course of acute ISA after second-generation DES remains unknown. OCT is a high-resolution (10 –20 mm) intracoronary imaging modality, which enables detailed in vivo assessment of individual strut apposition.2 Basic and clinical studies have reported the high accuracy and excellent reproducibility of OCT for an identification of ISA.3 – 5 The aim of the present study was to evaluate the natural course of acute ISA after second-generation everolimus-eluting stent (EES) when compared with the first-generation sirolimus-eluting stent (SES) by using OCT.
Methods Study population and protocol
OCT image acquisition A time-domain OCT system (Model M2 Cardiology Imaging System, LightLab Imaging, Inc., St Jude Medical, St Paul, MN, USA) was used in the present study. Images were acquired as previously reported.5 Briefly, a 0.016-inch OCT catheter (ImageWire, LightLab Imaging, Inc., St Jude Medical, St Paul, MN, USA) was advanced to the distal end of the DES-treated lesion through a 3F occlusion balloon catheter (Helios, Goodman Co., Ltd., Nagoya, Japan). To remove the blood from the field of view, the occlusion balloon was inflated at 0.4 –0.6 atmosphere at the proximal site of the DES-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. For the assessment of the proximal coronary arteries, a continuous-flushing (non-occlusive) technique of OCT imaging was used. To flush the vessel, a mixture of commercially available dextran 40 and lactated Ringer’s solution (low-molecular-weight Dextran L Injection, Otsuka Pharmaceutical Factory, Tokushima, Japan) was infused directly from the guiding catheter at a rate of 2.5 – 4.5 mL/s with an injector pump. Regardless of the OCT imaging technique used, the entire DES-treated lesion was imaged with an automatic pullback device travelling at 1 mm/s in all cases. 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 undertaken in a core laboratory (Wakayama Medical University, Wakayama, Japan) by an independent analysts blinded to stent-type allocation and clinical and procedural characteristics of the patients, using a dedicated off-line review system with a semiautomated contour-detection software (LightLab Imaging, Inc., St Jude Medical, St Paul, MN, USA). After calibration adjustment, OCT images were assessed to identify the ISA at intervals of 1 mm in the DES-treated lesions. When a strut was clearly separated from vessel wall, ISA distance was measured from the centre of the strut blooming to the adjacent lumen border. An incompletely apposed strut was defined as a strut with ISA distance .100 mm in EES and .170 mm in SES. This criterion was determined by adding the actual strut thickness and polymer thickness to the OCT resolution limit. The target site for OCT analysis in the present study was the site with maximal ISA distance at post-stenting. Serial OCT images at post-stenting and 8 – 12-month follow-up were reviewed side by side on the screen, and the target site was matched based on the distance from landmarks such as branches, calcifications, or stent edges. Cross-sectional areas of stent, intra-stent lumen, intra-stent tissue (defined as stent minus intra-stent lumen), and ISA (defined as extra-stent lumen) were measured at the target site. Intra-stent thrombus was identified as a mass protruding beyond the stent strut into the lumen with significant attenuation behind the mass.7 Representative serial OCT images of EES and SES are shown in Figure 1.
Coronary angiography Angiograms at post-stenting and 8 – 12-month follow-up were evaluated at one angiographic core laboratory (Cardiocore, Tokyo, Japan) with the use of CAAS 5.9 (Pie Medical Imaging, Maastricht, The Netherlands). The reference lumen diameter, minimum lumen diameter, and per cent diameter stenosis [(1 2 minimum lumen diameter/reference lumen diameter) × 100] were calculated. In-stent binary restenosis was defined as a diameter stenosis .50% at follow-up angiography.
Clinical outcomes The incidence of death, myocardial infarction, TLR and stent thrombosis was evaluated 8 –12 months after PCI. TLR was defined as any re-intervention (surgical or percutaneous) to treat in-stent restenosis.
Statistical analysis Statistical analysis was performed using the IBM SPSS Statistics software version 20.0 (SPSS, Inc., Chicago, IL, USA). Categorical variables were presented as frequencies, with comparisons using x2 statistics. Continuous variables were presented as mean + standard deviation and were compared using paired Student’s t-test (comparison between EES vs. SES) or unpaired Student’s t-test (comparison between post-stenting vs. follow-up). A P – value ,0.05 was considered statistically significant. Receiver-operating characteristic (ROC) curve analysis was used to identify the best cut-off value of OCT-estimated ISA distance at post-stenting for predicting late-persistent ISA at 8 – 12-month follow-up. The best cut-off value was determined by the maximum sum of sensitivity and specificity.
Results Patient characteristics Patient clinical characteristics are summarized in Table 1. There were no significant differences between EES and SES in terms of age, gender, coronary risk factors, clinical presentation at index procedure, stented coronary arteries, stent profiles (numbers of stents
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The Randomized Evaluation of Sirolimus-eluting vs. Everolimus-eluting stent Trial (RESET) was a prospective multi-centre randomized openTM label trial comparing EES (Xience V , Abbot Vascular, Inc., Santa Clara, TM CA, USA) with SES (Cypher Select-Plus , Cordis/Johnson & Johnson, Miami Lakes, FL, USA) in terms of target lesion revascularization (TLR) (ClinicalTrials.gov identifier NCT01035450).6 Details of the study protocols have been reported.6 The present study is a pre-specified imaging substudy of the RESET. OCT sites (n ¼ 16 centres) were pre-selected based on their willingness to participate in the imaging substudy of RESET. The patients were not randomly selected, but were selected by the OCT site investigators. Of the 3197 patients enrolled in RESET, 77 patients (EES ¼ 38 and SES ¼ 39) underwent serial OCT examination at post-stenting with optimization by post-dilatation and 8 – 12-month follow-up. The decision to carry out post-dilatation was made by the operator based on the angiographic images. The exclusion criteria for OCT were as follows: (i) apparent congestive heart failure, (ii) renal insufficiency (serum creatinine .2.0 mg/dL), and (iii) lesions unsuitable for OCT imaging (left main coronary artery lesions, ostial right coronary artery lesions, excessively tortuous vessel, and vessel size .4.0 mm). The study was approved by the institutional review board or medical ethics committee at each participating centre, and all the patients gave written informed consent.
K. Shimamura et al.
25
Incomplete stent apposition in DES
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Figure 1: Representative OCT images of EES and SES. ISA at post-stenting (arrows) resolved at follow-up in EES [(A) maximum ISA distance ¼ 370– 0 mm; ISA area ¼ 0.71 –0 mm2; intra-stent lumen area ¼ 7.18 – 5.91 mm2] and SES [(B) maximum ISA distance ¼ 260 – 0 mm; ISA area ¼ 0.79– 0 mm2; intra-stent lumen area ¼ 4.40– 3.66 mm2].
per lesion, stent diameter, total stent length per lesion), and other procedural characteristics. The mean duration between the index procedure and follow-up in EES and SES was 9.7 + 1.6 and 9.9 + 1.9 months, respectively. The recommended antiplatelet regimen included aspirin (≥81 mg daily) indefinitely and thienopyridines (75 mg clopidogrel or 200 mg ticlopidine daily) for at least 3 months.
QCA measurements QCA measurements at post-stenting and 8 –12-month follow-up are summarized in Table 2. During the follow-up period, the per cent diameter stenosis in the stented segment increased from 8.2 + 7.4 to 12.7 + 9.5% in EES (P ¼ 0.023) and from 8.8 + 6.2 to 13.2 + 10.2% in SES (P ¼ 0.007). Two patients in EES and three patients in
SES had in-stent binary restenosis and required TLR. There were no stent thrombosis, myocardial infarction, and cardiovascular death during the follow-up period.
OCT findings OCT images at post-stenting and 8–12-month follow-up were available for all patients. OCT findings are summarized in Table 3. ISA was observed in all EES and SES at post-stenting, and it was persistent in 26% of EES and 38% of SES at follow-up. Maximum ISA distance significantly decreased during the follow-up period in both EES (315 + 94 –110 + 165 mm, P , 0.001) and SES (308 + 119– 143 + 195 mm, P , 0.001). An intra-stent tissue area at follow-up was significantly greater in EES compared with SES (0.97 + 0.53 vs. 0.73 + 0.37 mm2, P , 0.001). The results of ROC curve analysis
26
K. Shimamura et al.
for predicting late-persistent ISA are shown in Figure 2. The best cut-off value of OCT-estimated ISA distance at post-stenting for predicting late-persistent ISA at 8–12-month follow-up in EES and SES was .355 and .285 mm, respectively. Maximum ISA distance was not different between ACS and stable AP in both EES (post-stenting: 301 + 93 vs. 320 + 96 mm, P ¼ 0.630; and 8–12-month follow-up: 51 + 145 vs. 125 + 169 mm, P ¼ 0.263) and SES (post-stenting: 281 + 63 vs. 314 + 128 mm, P ¼ 0.517; and 8– 12-month follow-up: 151 + 148 vs. 141 + 206 mm, P ¼ 0.897).
Discussion The main findings of this study were the following: (i) ISA was persistent in 26% of EES and 38% of SES at 8 –12-month follow-up; and (ii) The best cut-off value of OCT-estimated ISA distance at poststenting for predicting late-persistent ISA at 8–12-month follow-up in EES and SES was .355 and .285 mm, respectively. OCT can predict late-persistent ISA after DES implantation and provide useful information to optimize PCI.
Acute ISA Table 1
Patient clinical characteristics EES (n 5 38)
SES (n 5 39)
P-value
................................................................................ 67.1 + 9.5
69.1 + 9.0
0.308
Male gender, n (%) Coronary risk factors, n (%)
30 (79)
30 (77)
0.831
Hypertension
34 (89)
33 (85)
0.526
Dyslipidaemia Diabetes mellitus
31 (82) 18 (47)
30 (77) 16 (41)
0.615 0.575
Current smoker
19 (50)
20 (51)
0.910
30 (79)
32 (82)
8 (21)
7 (18)
Clinical presentation, n (%) Stable AP ACS
0.731
Stented coronary arteries, n (%) LAD 14 (37) LCX RCA Stent and procedure
0.409 20 (51)
9 (24)
6 (16)
15 (39)
13 (33) 1.2 + 0.5
Resolution of acute ISA
No. of stent per lesion
1.2 + 0.6
Stent diameter, mm Total stent length per lesion, mm
3.1 + 0.4 3.0 + 0.3 0.392 26.7 + 14.4 27.2 + 14.2 0.886
Direct stenting, n (%) Post-dilatation, n (%)
12 (32) 24 (63)
10 (26) 32 (82)
0.564 0.063
Maximum inflation pressure, atm
15.3 + 4.0
16.7 + 3.7
0.120
0.961
Values are given as n (%) or mean + standard deviation. AP, angina pectoris; ACS, acute coronary syndrome; EES, everolimus-eluting stent; LAD, left anterior-descending coronary artery; LCX, left circumflex coronary artery; RCA, right coronary artery; SES, sirolimus-eluting stent.
Table 2
The process of the resolution of acute ISA is initiated by growth of endothelial cells, and subsequent neointimal proliferation fills in the space between the ISA struts and the vessel wall.8 However, this re-endothelialization process is limited in time: it stops after 2–6 weeks in the animal models.12 Because the re-endothelialization stops after weeks or months, the neointima could fail to cover stent struts if the ISA space is large. OCT allows us to evaluate neointimal proliferation after DES in the clinical setting. Recent OCT studies showed that EES had greater neointimal proliferation than SES (mean neointimal hyperplasia thickness at 9 months after stent implantation: 115 + 52 vs. 89 + 58 mm, P ¼ 0.001) while there was no significant difference in in-stent restenosis and TLR between the two stents.13 An OCT study by Kawamori et al. 1 reported that the best cut-off values of ISA distance at post-stenting for predicting late-persistent ISA at 8-month follow-up in the first-
QCA measurements at post-stenting and 8 –12-month follow-up EES (n 5 38)
............................................................
SES (n 5 39)
............................................................
Post-stenting
Follow-up
P-value
Post-stenting
Follow-up
P-value
2.88 + 0.56 2.64 + 0.55
2.87 + 0.53 2.50 + 0.49
0.933 0.026
2.83 + 0.46 2.58 + 0.42
2.78 + 0.47 2.40 + 0.46
0.260 ,0.001
8.2 + 7.4
12.7 + 9.5
0.023
8.8 + 6.2
13.2 + 10.2
0.007
............................................................................................................................................................................... Reference lumen diameter, mm Minimum lumen diameter, mm Diameter stenosis, %
Values are given as mean + SD. EES, everolimus-eluting stent; QCA, quantitative coronary angiography; SES, sirolimus-eluting stent.
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Age, years
Acute ISA is mostly technique dependent and can occur after implantation of any type of stent. Acute ISA can resolve or persist at follow-up. Persistent ISA after DES implantation is associated with lessneointimalhyperplasia and presumably reduced re-endothelialization in comparison with acute ISA that resolves spontaneously.8 – 11 An OCT study reported that 77% of acute ISA in the first-generation DES resolved at 8-month follow-up.1 Acute ISA which will resolve spontaneously could be left without additional procedures including high-pressure post-dilation with large-diameter balloon.1 Therefore, elucidation of the natural course of acute ISA is important regarding the safety and cost-effectiveness of PCI. The present study demonstrated that the stent struts with ISA distance ,355 mm immediately after second-generation EES implantation could resolve spontaneously. These data might help us avoid unnecessary additional procedures frequently performed after stent implantation to achieve stent optimization.
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Incomplete stent apposition in DES
Table 3
OCT findings at post-stenting and 8 –12-month follow-up EES (n 5 38)
.............................................................. Post-stenting
SES (n 5 39)
.............................................................
Follow-up
P-value
Post-stenting
Follow-up
P-value
............................................................................................................................................................................... ISA, n (%)
38 (100)
10 (26)
,0.001
39 (100)
15 (38)
,0.001
Maximum ISA distance, mm
315 + 94
110 + 165
,0.001
308 + 119
143 + 195
,0.001
Stent area, mm2 Intra-stent lumen area, mm2
6.86 + 1.66 6.81 + 1.66
6.92 + 1.71 6.02 + 1.72
0.128 ,0.001
6.53 + 1.88 6.52 + 1.88
6.52 + 1.89 5.80 + 1.89
0.256 ,0.001
Intra-stent tissue area, mm2
0.08 + 0.12*
0.97 + 0.53*
,0.001
0.01 + 0.02
0.73 + 0.37
,0.001
ISA area, mm2
0.50 + 0.24*
0.17 + 0.27
,0.001
0.95 + 0.70
0.41 + 0.66
,0.001
Values are given as n (%) or mean + SD. EES, everolimus-eluting stent; ISA, incomplete stent apposition; OCT, optical coherence tomography; SES, sirolimus-eluting stent. *P , 0.05 vs. SES.
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Figure 2: Receiver-operating curve analysis for predicting late-persistent ISA. The best cut-off value of OCT-estimated ISA distance at poststenting for predicting late-persistent ISA at 8 – 12-month follow-up was .355 mm in EES [(A) sensitivity ¼ 100%; specificity ¼ 75%; positive predictive value ¼ 54%; negative predictive value ¼ 100%; area under the curve (AUC) ¼ 0.905] and .285 mm in SES [(B) sensitivity ¼ 93%; specificity ¼ 83%; positive predictive value ¼ 77%; negative predictive value ¼ 95%; AUC ¼ 0.947].
generation SES and paclitaxel-eluting stent were .280 and .260 mm, respectively. In the present study, we identified that the best cut-off value of OCT-estimated ISA distance at post-stenting for predicting late-persistent ISA in the second-generation EES was .355 mm. Acute ISA is easy to be resolved in the second-generation EES compared with the first-generation SES.
ISA and stent thrombosis The role of late ISA in the pathogenesis of late stent thrombosis remains controversial. A retrospective IVUS study by Cook et al. 14 demonstrated that the late-persistent or late-acquired ISA was more frequent (77 vs. 12%, P , 0.001) and the maximum ISA area was larger (8.3 + 7.5 vs. 4.0 + 3.8 mm2, P ¼ 0.03) in patients with
very late stent thrombosis compared with those without very late stent thrombosis after DES. Similarly, a case –control OCT study by Guagliumi et al. 15 showed that the frequency of late malapposed struts per patient was higher [4.60% (1.85–7.19%) vs. 1.81% (0.00– 2.99%), P , 0.001] and the maximum length of segments with malapposed struts was longer [1.40 mm (0.68–1.93 mm) vs. 0.00 mm (0.00–0.00 mm), P ¼ 0.001] in patients with late DES thrombosis compared with control subjects. We investigated late-persistent ISA by serial OCT examination at post-stenting and 8–12-month follow-up; however, the present study was not powered for evaluating stent thrombosis. Because the frequency of late and very late stent thrombosis is extremely low, a prospective study with a larger population and longer-time follow-up might be
28 needed to investigate the relationship between late ISA and stent thrombosis.
Limitations There are a number of limitations in the present study. First, although the intended OCT subsets represent the greater entire cohort of the RESET, they are derived only from centres specializing in OCT, and therefore are subject to some degree of selection bias. Second, we examined only EES and SES; therefore, our results cannot be applied to other DES. Third, the limited longitudinal resolution of OCT imaging may have biased the identification of corresponding images in serial (baseline and follow-up) OCT studies. Fourth, because we performed follow-up at only one point in time, further changes in the ISA are left to be clarified by the repeated follow-up studies. Fifth, the relationship between late-persistent ISA detected by OCT and the risk of adverse clinical events, stent thrombosis in particular, needs to be demonstrated in a prospective long-term study with a larger sample size. Finally, late-acquired ISA was beyond the scope of our study. Further studies are required to assess the frequency, mechanisms, and clinical implications of late-acquired ISA.
Conclusions
Acknowledgements We thank Yoichi Nozaki, MD, Hiroyuki Kyono, MD, Tsukasa Inada, MD, Mitsuru Abe, MD, Kazushi Urasawa, MD, and Yukio Ozaki, MD for OCT image collections. Conflict of interest: T.K., K.I., and K.K. were advisory board members of Abbott Vascular. The other authors do not have a conflict of interest in the context of the subject of this article.
Funding This study was funded by Abbott Vascular.
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Compared the first-generation with SES, the second-generation EES showed more favourable vascular response in the resolution of acute ISA. OCT can predict late-persistent ISA after DES implantation and provide useful information to optimize PCI.
K. Shimamura et al.
