European Heart Journal – Cardiovascular Imaging (2015) 16, 513–520 doi:10.1093/ehjci/jeu227
Comparison of vascular response between everolimus-eluting stent and bare metal stent implantation in ST-segment elevation myocardial infarction assessed by optical coherence tomography Yasushi Ino, Takashi Kubo*, Atsushi Tanaka, Yong Liu, Takashi Tanimoto, Hironori Kitabata, Yasutsugu Shiono, Kunihiro Shimamura, Makoto Orii, Kenichi Komukai, Keisuke Satogami, Yoshiki Matsuo, Takashi Yamano, Tomoyuki Yamaguchi, Kumiko Hirata, Toshio Imanishi, and Takashi Akasaka Department of Cardiovascular Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan
Aims
The long-term safety of second-generation everolimus-eluting stents (EESs) in ST-segment elevation myocardial infarction (STEMI) remains unclear. The aim of this study was to evaluate the late vascular response after stent implantation in STEMI between EES and bare-metal stent (BMS) by using optical coherence tomography (OCT). ..................................................................................................................................................................................... Methods A prospective OCT examination was performed in 102 patients at 10 months after stent implantation for treatment of and results STEMI. A total of 1253 frames with 12 772 struts in 61 EESs and 776 frames with 8594 struts in 41 BMSs were analysed. There were no significant differences in the percentage of uncovered struts (2.1 + 2.8 vs. 1.7 + 2.7%, P ¼ 0.422) and malapposed struts (0.7 + 1.3 vs. 0.6 + 1.2%, P ¼ 0.756) between EES and BMS. The frequency of intra-stent thrombus was comparable between the two stents (13 vs. 10%, P ¼ 0.758). The mean neointimal thickness was smaller in EES compared with BMS (104 + 39 vs. 388 + 148 mm, P , 0.001). In-segment binary restenosis and target lesion revascularization was less often seen in EES compared with BMS (3 vs. 17%, P ¼ 0.028 and 2 vs. 12%, P ¼ 0.037, respectively). ..................................................................................................................................................................................... Conclusion When compared with BMS, EES showed a lower rate of stent restenosis, similar frequency of neointimal coverage, stent malapposition, and intra-stent thrombus at 10 months after stent implantation in STEMI. Our results suggest the safety and effectiveness of EES in primary percutaneous coronary intervention for STEMI patients.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Everolimus-eluting stent † ST-segment elevation myocardial infarction † Stent malapposition † Optical coherence tomography
Introduction The safety and efficacy of bare-metal stents (BMS) have been established in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).1,2 The first-generation drug-eluting stents (DES) have dramatically reduced in-stent restenosis (ISR) and target lesion
revascularization (TLR) after primary PCI in comparison with BMS.3 – 5 However, concerns have been raised regarding the longterm safety of DES in STEMI. Pathological studies reported that the implantation of first-generation DES in unstable coronary lesions might delay arterial healing and impair stent endothelialization.6 – 8 In addition, an optical coherence tomography (OCT) study at 13 months after primary PCI for STEMI demonstrated
* Corresponding author. Tel: +81 73 441 0621; fax: +81 73 446 0631, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
Downloaded from by guest on May 21, 2015
Received 24 May 2014; accepted after revision 27 October 2014; online publish-ahead-of-print 26 November 2014
514 that first-generation DES had a higher rate of uncovered struts with neointima and incomplete stent apposition in comparison with BMS.9 Recently, second-generation DES, such as the everolimuseluting stent (EES), have been developed to improve the safety profile by means of more biocompatible polymers, reduced drug dose with adapted release kinetics, and reduced strut thickness.10 Some clinical trials have demonstrated the superior efficacy of EES in STEMI compared with BMS and first-generation DES.11 – 13 We therefore evaluated the late vascular response and long-term safety of second-generation EES in STEMI when compared with BMS by using OCT.
Methods
Y. Ino et al.
OCT image acquisition Patients were administered intravenous heparin (5000 IU) and intracoronary isosorbide dinitrate (2 mg) prior to the OCT procedure. Frequency-domain (FD)-OCT imaging system (C7-XRTM , St. Jude Medical, St. Paul, MN, USA) was used in the present study. Following a Z-offset adjustment, an FD-OCT image catheter (DragonflyTM imaging catheter, St Jude Medical, St Paul, MN, USA) was advanced distally to the stented segment over a 0.014-inch conventional angioplasty guidewire. After the catheter placement, preheated contrast media at 378C (OmnipaqueTM 350 Injection, Daiichi Pharmaceutical, Tokyo, Japan) was flushed through the guiding catheter at a rate of 2 – 4 mL/s for 3 – 6 s using an injector pump (Mark V; Medrad, PA, USA). When a blood-free image was observed, the FD-OCT imaging core was withdrawn up to 50 mm at a rate of 20 mm/s using the stand-alone electronic control of the pullback motor. FD-OCT images were stored digitally for subsequent analysis.
Study design
Coronary angiography Coronary angiography was carried out in the standard manner. Quantitative coronary angiographic analysis was performed using a validated automated edge detection algorithm (CAAS-5, Pie Medical, Maastricht, Netherlands) by experienced investigators (T.T. or Y.S.) who were blinded to the clinical information and OCT findings. The reference vessel diameter, minimal luminal diameter (MLD) of the lesion, and per cent diameter stenosis were measured in the view that was the most severe and not foreshortened. Acute gain was defined as the difference between the post-procedure MLD and the pre-procedure MLD. In-stent late loss was defined as the difference between the in-stent MLD at post-stenting and at follow-up. In-segment binary restenosis was defined as a percent diameter stenosis .50% in the stented segment plus the margins 5 mm proximal and distal to the stent at follow-up.
OCT analysis All OCT images were analysed by experienced investigators (K.S. or L.Y.) who were blinded to the clinical information and angiographic findings. FD-OCT analysis was performed using a dedicated off-line review system with semi-automated contour-detection software (St Jude Medical, St Paul, MN, USA). The Z-offset was adjusted again before FD-OCT analysis. All cross-sectional images (frames) were initially screened to assess quality. Inadequate images, including poor quality caused by residual blood or artefact, and bifurcations of side branches were excluded from the analyses.14 – 16 Stent-overlap segments were also excluded because of incorrect traces of the outer stent due to the limited penetration depth of OCT images and backscattering by the inner stent struts. Qualitative imaging assessment was performed at every frame to detect the presence of intra-stent thrombus. Because the distinction between fibrin clots and neointimal hyperplasia after DES implantation is sometimes impossible, only masses protruding through the stent struts into the lumen with OCT-signal backscattering and attenuation were defined as intra-stent thrombus.9,14 – 16 In order to avoid misclassification of small image artefacts, only protruding masses .250 mm diameter were included.9 Quantitative strut-level analysis was performed at 1 mm intervals along the entire stented segment. Neointimal coverage was assessed on each individual strut. If neointimal coverage of the strut was observed, neointimal thickness on each strut was measured from the neointimal surface to the centre of the strut blooming. An uncovered strut was defined as a strut with a measured neointimal thickness equal to 0 mm. A malapposed strut was defined as a strut with a distance between the centre of the strut blooming and the adjacent lumen border ≥110 mm in both EES and BMS. This criterion was determined by adding the actual strut thickness and polymer thickness to the OCT resolution limit (EES: 81 + 7.8 + 20 ¼ 108.8 mm; BMS: 81 + 20 ¼ 101 mm). The maximum length of the segment with uncovered struts (or malapposed struts) was estimated as [the number of cross-sections with uncovered struts (or malapposed struts)] × [longitudinal interval between the analysed cross-sections (1 mm)]. Each stent strut condition was classified into one of the four categories (Figure 1):9,16 (a) well apposed to the vessel wall with neointimal coverage on the strut; covered and apposed strut, (b) incompletely apposed to the vessel wall with neointimal coverage; covered and malapposed strut, (c) well apposed to the vessel wall without neointimal coverage; uncovered and apposed strut, and (d) incompletely apposed to the vessel wall without neointimal coverage; uncovered and malapposed strut. Intra- and interobserver variability for the stent strut condition were assessed in the randomly selected 10
Downloaded from by guest on May 21, 2015
The inclusion criteria in the present study were admission to our hospital within 12 h from the onset of the symptom, a diagnosis of STEMI, and requiring primary PCI for a de novo culprit lesion in a native coronary artery. The clinical diagnosis of STEMI was based on the concurrence of all three following criteria: (i) continuous chest pain for at least 30 min, (ii) ST-segment elevation ≥0.1 mV in two or more contiguous leads on a 12-lead electrocardiogram, (iii) elevated myocardial enzymes [serum creatine kinase-MB (myocardial band) fraction levels more than two times higher than normal]. Exclusion criteria were left main disease, ostial right coronary artery lesions, renal insufficiency with baseline serum creatinine .2.0 mg/dL, the age younger than 20 years, cardiogenic shock, and inability to comply with dual-antiplatelet therapy and follow-up requirements. This was a prospective, open-label, non-randomized, single-centre study in Wakayama Medical University. The study had two periods. In the first period (between January 2011 and July 2011), patients with STEMI requiring primary PCI were assigned to Multilink Vision BMS (Abbott Vascular, Santa Clara, CA, USA) implantation. In the second period (between August 2011 and January 2012), patients with STEMI requiring primary PCI were assigned to Xience V EES (Abbott Vascular, Santa Clara, CA, USA) implantation. Angiographic and OCT follow-up was scheduled at 10 months after primary PCI to compare the late vascular response after stent implantation in STEMI between EES and BMS. All patients received dual-antiplatelet therapy with aspirin (100 mg/day) and clopidogrel (75 mg/day) for 12 months after primary PCI. The study protocol was approved by the Wakayama Medical University Ethics Committee, and all patients provided informed consent before participation.
515
Vascular response of EES and BMS in STEMI
Figure 1 Each stent strut condition. Each stent strut condition was classified as covered and apposed strut (A), covered and malapposed strut (B), uncovered and apposed strut (C), and uncovered and malapposed strut (D).
Statistical analysis Statistical analysis was performed with Stat View 5.0J (SAS Institute, Cary, NC, USA). Categorical variables were presented as frequencies, with comparison using x2 statistics or Fisher’s exact test (if the expected cell value was ,5). Normally distributed continuous variables were presented as mean + SD and were compared using unpaired Student’s t-tests; non-normally distributed continuous variables were presented as median (interquartile range) and were compared with the Mann– Whitney U test. A P-value of ,0.05 was considered statistically significant.
Results Baseline clinical characteristics Primary PCI was performed in 133 patients with STEMI during the study period (53 patients in the first period and 80 patients in the second period). Of these, we released 18 patients (7 and 11 patients) according to the exclusion criteria. Furthermore, we excluded nine patients (three and six patients) due to refusal of the scheduled followup angiography, two patients with non-cardiac death (EES ¼ 1 and BMS ¼ 1), and two patients (EES ¼ 1 and BMS ¼ 1) with subacute stent thrombosis. These subacute stent thrombosis events occurred at 12 and 9 days after stent implantation and caused non-fatal myocardial reinfarction. Thus, 102 patients (EES ¼ 61 and BMS ¼ 41) were assessed in the present study. Patient clinical characteristics are shown in Table 1. Age, gender, coronary risk factors, and peak levels of cardiac enzymes were similar between EES and BMS. The median time from stent implantation to follow-up OCT imaging in EES and BMS was 10.0 months
Table 1
Patient clinical characteristics EES (n 5 61)
BMS (n 5 41)
P-value
Age (years)
67 + 11
65 + 9
0.256
Male, n (%) Coronary risk factors
46 (75)
34 (83)
0.366
Hypertension, n (%)
49 (80)
31 (76)
0.570
Dyslipidaemia, n (%) Diabetes mellitus, n (%)
46 (75) 22 (36)
30 (73) 14 (34)
0.799 0.842
Cigarette smoking, n (%)
34 (56)
27 (66)
0.307
................................................................................
Cardiac enzyme at baseline Peak creatinine kinase 3115 + 1880 3347 + 2286 (IU/L) Peak creatinine kinase MB 313 + 170 338 + 269 (IU/L) Medications at follow-up
0.577 0.557
Aspirin, n (%)
61 (100)
41 (100)
1.000
Thienopiridine, n (%) Statin, n (%)
59 (97) 52 (85)
39 (95) 37 (90)
0.999 0.551
ACEI/ARB, n (%)
53 (87)
38 (93)
0.518
Calcium antagonist, n (%) 17 (28) b-Blocker, n (%) 37 (61)
9 (22) 28 (68)
0.501 0.432
Total cholesterol (mg/dL) 161 + 29 LDL-cholesterol (mg/dL) 88 + 24
156 + 30 82 + 21
0.486 0.182
HDL-cholesterol (mg/dL) 43 + 11
Laboratory data at follow-up
44 + 12
0.741
138 + 85 116 + 31
145 + 99 122 + 43
0.665 0.441
HbA1C (%)
6.2 + 1.5
6.4 + 1.7
0.421
hs-CRP (mg/L)
0.9 + 0.7
0.1 + 0.1
0.180
Triglyceride (mg/dL) Fasting glucose (mg/dL)
Values are given as n (%) or mean + standard deviation. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BMS, bare-metal stent; EES, everolimus-eluting stent; HDL, high-density lipoprotein; hs-CRP, high-sensitive C-reactive protein; LDL, low-density lipoprotein; MB, myocardial band.
(9.5 and 10.5) and 10.0 months (9.3 and 10.8), respectively (P ¼ 0.925). The medications and laboratory data at follow-up were not different between the two groups.
Downloaded from by guest on May 21, 2015
stent-treated lesions (EES ¼ 5 and BMS ¼ 5) and showed excellent concordance (k ¼ 0.92 and 0.90, respectively). 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 within the stent. The volume was calculated with the use of Simpson’s rule. Reproducibility of neointimal thickness and volume measurement was assessed in the randomly selected 10 stent-treated lesion (EES ¼ 5 and BMS ¼ 5). There was a good correlation for the repeated measurements by the same observer (r ¼ 0.991 and 0.987, respectively) and two different observers (r ¼ 0.992 and 0.989, respectively).
516
Y. Ino et al.
Angiographic and procedural characteristics Angiographic findings and procedural characteristics are shown in Table 2. Angiographic findings at pre-intervention were similar between the two groups. Stent diameter was smaller (3.17 + 0.34 vs. 3.49 + 0.34 mm, P , 0.001) and stent length was longer (22 + 6 vs. 19 + 4 mm, P ¼ 0.004) in EES compared with BMS. Although MLD at post-intervention was smaller in EES, MLD at follow-up was significantly greater in EES compared with BMS (2.86 + 0.57 vs. 2.16 + 0.77 mm, P , 0.001). Percent diameter stenosis at
Table 2 Angiographic findings and procedural characteristics BMS (n 5 41)
P-value
LAD/LCX/RCA TIMI flow grade 0/1/2/3
32/8/21 33/8/11/9
20/5/16 25/2/10/4
0.894 0.413
Ulceration
14 (23)
9 (22)
0.999
Thrombus Reference vessel diameter (mm) Minimum lumen diameter (mm) Percent diameter stenosis (%) Lesion length (mm)
44 (72) 3.10 + 0.46
31 (76) 3.23 + 0.38
0.696 0.156
0.18 + 0.24
0.15 + 0.28
0.575
94 + 8
96 + 8
0.247
16 + 8
15 + 5
0.431
Stent diameter (mm) Stent length (mm)
3.17 + 0.34 22 + 6
3.49 + 0.34 19 + 4
................................................................................ Pre-intervention
Stents and procedures ,0.001 0.004
Stent to artery ratio
1.05 + 0.08
1.08 + 0.12
0.111
Maximal pressure (atm) Thrombectomy, n (%)
16 + 4 47 (77)
16 + 4 32 (78)
0.299 0.906
Direct stenting, n (%)
10 (16)
6 (15)
0.811
Onset to balloon time (min)
278 + 125
289 + 149
0.679
Minimum lumen diameter (mm)
3.01 + 0.41
3.27 + 0.38
0.002
Percent diameter stenosis (%)
4+4
5+3
0.111
OCT findings The follow-up OCT examination was successfully performed in all patients. Of all recorded frames in the stent-treated lesion, 2.2% in EES and 2.4% in BMS (P ¼ 0.756) were excluded from the analysis due to inadequate images, bifurcations, or stent overlapping segments. We analysed a total of 1253 frames with 12 772 struts in EES and 776 frames with 8594 struts in BMS. Frequency distribution of neointimal thickness on stent struts is shown in Figure 2. Approximately 98% of struts were covered by neointima in both EES and BMS. The median neointimal thickness was significantly smaller in EES compared with BMS (80 mm (50 and 130) vs. 350 mm (190 and 540), P , 0.001). The OCT findings at 10-month follow-up are shown in Table 3. In the stent-treated lesion-level analysis, the stent strut conditions, such as percentage of uncovered struts and malapposed struts, were not different between EES and BMS. The frequency of lesions with any uncovered struts (49 vs. 34%, P ¼ 0.133) and the maximum length of segments with uncovered struts (P ¼ 0.151) were similar between the two stents. The frequency of lesions with any malapposed struts (34 vs. 22%, P ¼ 0.175) and the maximum length of segments with malapposed struts (P ¼ 0.215) were also comparable between the two stents. Furthermore, the frequency of intra-stent thrombus was not different between EES and BMS (13 vs. 10%, P ¼ 0.758). In the morphometric analysis, although the minimum stent area was smaller (P ¼ 0.003) in EES, the minimum lumen area was larger (P , 0.001), and the maximum neointimal area was smaller (P , 0.001) in EES compared with BMS. There was no difference in the maximum malapposition area and the malapposition volume between EES and BMS. Representative OCT images of EES and BMS are shown in Figures 3 and 4, respectively.
Post-intervention
10-month follow-up Minimum lumen diameter (mm) Percent diameter stenosis (%) In-stent late loss (mm) In-segment binary restenosis, n (%) Target lesion revascularization, n (%)
Discussion Healing delay after DES
2.86 + 0.57
2.16 + 0.77
,0.001
8 + 10
38 + 22
,0.001 ,0.001
0.15 + 0.38
1.11 + 0.68
2 (3)
7 (17)
0.028
1 (2)
5 (12)
0.037
Values are given as n (%) or mean + standard deviation. BMS, bare-metal stent; EES, everolimus-eluting stent; LAD, left anterior descending; LCX, left circumflex; RCA, right coronary artery; TIMI, Thrombolysis In Myocardial Infarction.
First-generation DES has dramatically reduced ISR and TLR after primary PCI for STEMI in comparison with BMS.3 – 5 Nevertheless, concerns have been raised regarding the long-term safety after DES in STEMI. Pathological studies reported that first-generation DES implantation in unstable coronary lesions might delay arterial healing and impair stent endothelialization.6 – 8 Because sirolimus and paclitaxel are highly lipophilic, it is likely that these agents have high affinity for lipid-rich plaques, dwell there for long periods of time, and influence healing by retarding smooth muscle cell proliferation and endothelial regrowth. In addition, the lipid-rich necrotic cores are more avascular compared with the fibrous dominant plaques and have fewer cells. Therefore, these areas might be less likely to be covered by migrating and proliferating cells from adjacent areas. Finn et al. demonstrated that a ratio of uncovered to total stent
Downloaded from by guest on May 21, 2015
EES (n 5 61)
follow-up (8 + 10 vs. 38 + 22%, P , 0.001) and in-stent late loss (0.15 + 0.38 vs. 1.11 + 0.68 mm, P , 0.001) were significantly smaller in EES compared with BMS. In-segment binary restenosis was observed in two cases in EES and seven cases in BMS (3 vs. 17%, P ¼ 0.028). Target lesion revascularization was performed in one case in EES and five cases in BMS (2 vs. 12%, P ¼ 0.037). There was no case with late-stent thrombosis in the present study.
517
Vascular response of EES and BMS in STEMI
Figure 2 The frequency distributions of the neointimal thickness at intervals of 50 mm. Struts with a neointimal thickness of 60– 100 mm were most frequently observed in EES, whereas the neointimal thickness in BMS was widely distributed. BMS, bare-metal stent; EES, everolimus-eluting stent.
Table 3
OCT findings at 10-month follow-up BMS (n 5 41)
P-value
Stent-treated lesion-level analysis Stent strut condition Uncovered struts (%)
2.1 + 2.8
1.7 + 2.7
0.422
Malapposed struts (%) Covered and apposed struts (%)
0.7 + 1.3 97.8 + 3.0
0.6 + 1.2 98.4 + 2.7
0.756 0.366
Covered and malapposed struts (%)
0.1 + 0.2
0.1 + 0.3
0.947
Uncovered and apposed struts (%) Uncovered and malapposed struts (%)
1.6 + 2.3 0.6 + 1.2
1.2 + 2.0 0.4 + 0.9
0.379 0.596
Lesion with any uncovered struts, n (%)
30 (49)
14 (34)
0.133
Maximum length of segment with uncovered struts (mm) Lesion with any malapposed struts, n (%)
0.9 + 1.3 21 (34)
0.6 + 0.8 9 (22)
0.151 0.175
0.5 + 0.8
0.3 + 0.6
0.215
8 (13)
4 (10)
0.758
Maximum length of segments with malapposed struts (mm) Intra-stent thrombus, n (%) Morphometric analysis Minimum stent area (mm2)
6.57 + 1.95
7.74 + 1.79
0.003
Maximum neointimal area (mm2) Minimum lumen area (mm2)
1.83 + 0.99 5.61 + 1.91
5.49 + 1.84 3.60 + 1.85
,0.001 ,0.001
Maximum malapposition area (mm2)
0.11 + 0.26
0.13 + 0.32
Stent volume (mm3) Neointimal volume (mm3)
158.78 + 51.54 19.10 + 11.82
175.78 + 65.66 71.60 + 43.37
0.147 ,0.001
Lumen volume (mm3)
139.47 + 48.59
104.17 + 41.68
,0.001
Malapposition volume (mm3)
0.19 + 0.42
0.18 + 0.43
0.688
0.925
Values are given as n (%) or mean + standard deviation. BMS, bare-metal stent; EES, everolimus-eluting stent; OCT, optical coherence tomography.
struts per section .30% was the most powerful predictor of stent thrombosis.8 The efficacy of first-generation DES use in primary PCI for STEMI may be offset by an increased risk of stent thrombosis and accompanying clinical outcomes due to delayed arterial healing.
Second-generation DES Second-generation EES has been developed to improve the safety and efficacy of coronary stents by modifying the eluted drug, drug carrying system, and stent design.10,12 EES is a cobalt chromium
Downloaded from by guest on May 21, 2015
EES (n 5 61)
...............................................................................................................................................................................
518
Y. Ino et al.
alloy stent with thin (81 mm) strut thickness, which is coated with a thin (7.8 mm), non-adhesive, durable, biocompatible fluorinated copolymer releasing a reduced dose of everolimus compared with the dose used in first-generation DES. Therefore, EES implantation may introduce a more favourable vascular response. Furthermore, the EES uses a fluorinated copolymer, which comprises vinylidene fluoride and hexafluoropropylene monomers that might confer a certain degree of thromboresistance and haemocompatibility.17 This benefit of low thrombogenicity of EES may even be extended to uncovered and/or malapposed stent struts.
EES in AMI Previous clinical studies and meta-analyses reported that firstgeneration DES in primary PCI for STEMI increased the risk of very late stent thrombosis despite a reduction in target vessel revascularization.18,19 The OCT sub-study of the HORIZONS-AMI trial showed that implantation of the first-generation paclitaxel-eluting stent in AMI significantly reduced neointimal hyperplasia, but resulted in higher rates of uncovered and malapposed stent struts at 13-month follow-up in comparison with BMS.9 Recently, the XAMI trial demonstrated that second-generation EES was superior to SES
for major adverse cardiac event-free survival at 1 year in patients with AMI.11 The EXAMINATION trial indicated that EES in STEMI reduced not only TLR, but also stent thrombosis in comparison with BMS.12 A recent OCT study has demonstrated that EES when compared with first-generation DES has more favourable late vascular response in stable coronary artery disease.20 In AMI, however, an OCT study assessing the late vascular response and long-term safety after EES has been lacking. The present OCT study demonstrated that the extent of neointimal coverage after EES in STEMI was similar to that after BMS. In addition, the incidence of uncovered struts, malapposed struts, and intra-stent thrombus after EES in the present study was lower than that after first-generation DES reported in the previous OCT studies.9,21 This favourable vascular response after EES was thought to be owing to low drug dose, biocompatibility of polymers, and the fluorinated copolymer. Our data support the favourable results of the recent clinical trials of EES for STEMI, suggesting safety and efficacy of EES for primary PCI in STEMI patients. On the other hand, even if 98% of all struts were covered in both EES and BMS at follow-up, and lesions with any uncovered struts did not differ between EES and BMS (49 and 34%), it cannot be excluded a
Downloaded from by guest on May 21, 2015
Figure 3 Representative OCT images of EES at 10-month follow-up. Angiography showed no intra-stent restenosis in the right coronary artery (A, arrow). Cross-sectional OCT images visualized well apposed struts with neointimal coverage (B – D). EES, everolimus-eluting stent; OCT, optical coherence tomography.
Vascular response of EES and BMS in STEMI
519
possible clustering distribution of non-coverage strut, for example: some particular concentration of uncovered struts in some patients or in some regions within stent. Moreover, it has to be considered that also individual, mechanical, and loco-regional factors (levels of circulating endothelial progenitor cells or regional shear stress) can play a role in neointimal healing and the only differences in percentage coverage cannot be always advocated to explain the clinical results regarding stent thrombosis.22
Study limitations The present study has several limitations. First, the major limitation of the present study is the suboptimal simplified statistical analysis of such a complex OCT dataset. The applied analyses are inappropriate for clustered data and the results should be considered just as an approximation. Second, this is a non-randomized, single-centre study with a relatively small study population, which may cause selection bias. The decision of stent diameter and length was left to the operator, and this might have played a role in the difference in size of EES with respect to BMS. In fact, although reference vessel size was similar, EES was smaller and longer compared with BMS. In several
studies, small vessels and small stents show better coverage than large vessels and large stents. The stent size in EES might contribute the better coverage partially. Third, some cross-sections were excluded from the OCT analysis. However, those were only 2.2% in EES and 2.4% in BMS of all recorded frames (P ¼ 0.756). Fourth, in this study, a single criterion of malapposition in both EES and BMS has been chosen. Therefore, in BMS (without polymer thickness), malappositions might have been underestimated with respect to EES. However, the difference was small (only 7.8 mm) and under the OCT resolution limit. Fifth, endothelial cell dimensions are below the resolution of OCT. Some struts appearing bare may have been covered by endothelium, and thus, misclassified. Sixth, OCT data before and immediately after stent implantation were not available. Therefore, it was unclear whether the stent malapposition and intra-stent thrombus were persistent or late acquired. Finally, this study was not powered or not designed to assess the relationship between suboptimal stent results as determined by the follow-up OCT examination and future development of stent thrombosis. Further studies are required to investigate the clinical implications of OCT findings at 10 months after stent implantation.
Downloaded from by guest on May 21, 2015
Figure 4 Representative OCT images of BMS at 10-month follow-up. Angiography showed in-stent restenosis in the mid portion of right coronary artery (A, arrow). Cross-sectional OCT images visualized thick neointima in the stented segment (B – D). BMS, bare-metal stent; OCT, optical coherence tomography.
520
Y. Ino et al.
Conclusions When compared with BMS, EES showed a lower rate of stent restenosis and similar frequency of neointimal stent coverage, stent malapposition, and intra-stent thrombus at 10 months after stent implantation for treatment of STEMI. Our results suggest the safety and effectiveness of EES in primary PCI for STEMI patients.
12.
13.
Conflict of interest: none declared.
References
14. 15.
16. 17.
18.
19.
20.
21.
22.
Downloaded from by guest on May 21, 2015
1. Grines CL, Cox DA, Stone GW, Garcia E, Mattos LA, Giambartolomei A et al. Coronary angioplasty with or without stent implantation for acute myocardial infarction. Stent Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 1999; 341:1949 –56. 2. De Luca G, Suryapranata H, Stone GW, Antoniucci D, Biondi-Zoccai G, Kastrati A et al. Coronary stenting versus balloon angioplasty for acute myocardial infarction: a meta-regression analysis of randomized trials. Int J Cardiol 2008;126:37 –44. 3. Spaulding C, Henry P, Teiger E, Beatt K, Bramucci E, Carrie´ D et al. Sirolimus-eluting versus uncoated stents in acute myocardial infarction. N Engl J Med 2006;355: 1093 –104. 4. Stone GW, Lansky AJ, Pocock SJ, Gersh BJ, Dangas G, Wong CS et al. Paclitaxeleluting stents versus bare-metal stents in acute myocardial infarction. N Engl J Med 2009;360:1946 – 59. 5. Kastrati A, Dibra A, Spaulding C, Laarman GJ, Menichelli M, Valgimigli M et al. Meta-analysis of randomized trials on drug-eluting stents vs. bare-metal stents in patients with acute myocardial infarction. Eur Heart J 2007;28:2706 –13. 6. Nakazawa G, Finn AV, Joner M, Ladich E, Kutys R, Mont EK et al. 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. 7. Finn AV, Nakazawa G, Ladich E, Kolodgie FD, Virmani R. Does underlying plaque morphology play a role in vessel healing after drug eluting stent implantation? JACC Cardiovasc Imaging 2008;1:485 –8. 8. Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 2007;115:2435 – 41. 9. Guagliumi G, Costa MA, Sirbu V, Musumeci G, Bezerra HG, Suzuki N et al. Strut coverage and late malapposition with paclitaxel-eluting stents compared with bare metal stents in acute myocardial infarction: optical coherence tomography substudy of the HORIZONS-AMI Trial. Circulation 2011;123:274 –81. 10. Palmerini T, Kirtane AJ, Serruys PW, Smits PC, Kedhi E, Kereiakes D et al. Stent thrombosis with everolimus-eluting stents: meta-analysis of comparative randomized controlled trials. Circ Cardiovasc Interv 2012;5:357 –64. 11. Hofma SH, Brouwer J, Velders MA, van’t Hof AW, Smits PC, Quere´ M et al. Secondgeneration everolimus-eluting stents versus first-generation sirolimus-eluting stents
in acute myocardial infarction: 1-year results of the randomized XAMI (XienceV Stent vs. Cypher Stent in Primary PCI for Acute Myocardial Infarction) trial. J Am Coll Cardiol 2012;60:381 –7. Sabate M, Cequier A, In˜iguez A, Serra A, Hernandez-Antolin R, Mainar V et al. Everolimus-eluting stent versus bare-metal stent in ST-segment elevation myocardial infarction (EXAMINATION): 1 year results of a randomised controlled trial. Lancet 2012;380:1482 –90. Bangalore S, Amoroso N, Fusaro M, Kumar S, Feit F. Outcomes with various drug-eluting or bare metal stents in patients with ST-segment –elevation myocardial infarction: a mixed treatment comparison analysis of trial level data from 34068 patient-years of follow-up from randomized trials. Circ Cardiovasc Interv 2013;6: 378 –90. Kubo T, Akasaka T. Optical coherence tomography imaging: current status and future perspectives. Cardiovasc Interv Ther 2010;25:2 –10. Park J, Shin DH, Kim BK, Her AY, Kim YH, Choi HH et al. Relationship between aspirin/clopidogrel resistance and intra-stent thrombi assessed by follow-up optical coherence tomography after drug-eluting stent implantation. Eur Heart J Cardiovasc Imaging 2013;14:1181 – 6. Lowe HC, Narula J, Fujimoto JG, Jang IK. Intracoronary optical diagnostics current status, limitations, and potential. JACC Cardiovasc Interv 2011;4:1257 –70. Kolandaivelu K, Swaminathan R, Gibson WJ, Kolachalama VB, Nguyen-Ehrenreich KL, Giddings VL et al. Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation 2011;123:1400 –9. Kalesan B, Pilgrim T, Heinimann K, Ra¨ber L, Stefanini GG, Valgimigli M et al. Comparison of drug-eluting stents with bare metal stents in patients with ST-segment elevation myocardial infarction. Eur Heart J 2012;33:977 –87. Jensen LO, Maeng M, Thayssen P, Kaltoft A, Tilsted HH, Bøttcher M et al. Clinical outcome after primary percutaneous coronary intervention with drug-eluting and bare metal stents in patients with ST-segment elevation myocardial infarction. Circ Cardiovasc Interv 2008;1:176 – 84. Toledano Delgado FJ, Alvarez-Ossorio MP, de Lezo Cruz-Conde JS, Bellido FM, Romero Moreno MA, Ferna´ndez-Aceytuno AM et al. Optical coherence tomography evaluation of late strut coverage patterns between first-generation drug-eluting stents and everolimus-eluting stent. Catheter Cardiovasc Interv 2013; doi:10.1002/ccd.25235. Gonzalo N, Barlis P, Serruys PW, Garcia-Garcia HM, Onuma Y, Ligtheart J et al. Incomplete stent apposition and delayed tissue coverage are more frequent in drug-eluting stents implanted during primary percutaneous coronary interventions for ST-segment elevation myocardial infarction then in drug-eluting stents implanted for stable/unstable angina: insights from optical coherence tomography. JACC Cardiovasc Interv 2009;2:445–52. Gutie´rrez-Chico JL, van Geuns RJ, Regar E, van der Giessen WJ, Kelbæk H, Saunama¨ki K et al. Tissue coverage of a hydrophilic polymer-coated zotarolimuseluting stent vs. a fluoropolymer-coated everolimus-eluting stent at 13-month follow-up: an optical coherence tomography substudy from the RESOLUTE All Comers trial. Eur Heart J 2011;32:2454 –63.
Comparison of vascular response between everolimus-eluting stent and bare metal stent implantation in ST-segment elevation myocardial infarction assessed by optical coherence tomography Yasushi Ino, Takashi Kubo*, Atsushi Tanaka, Yong Liu, Takashi Tanimoto, Hironori Kitabata, Yasutsugu Shiono, Kunihiro Shimamura, Makoto Orii, Kenichi Komukai, Keisuke Satogami, Yoshiki Matsuo, Takashi Yamano, Tomoyuki Yamaguchi, Kumiko Hirata, Toshio Imanishi, and Takashi Akasaka Department of Cardiovascular Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan
Aims
The long-term safety of second-generation everolimus-eluting stents (EESs) in ST-segment elevation myocardial infarction (STEMI) remains unclear. The aim of this study was to evaluate the late vascular response after stent implantation in STEMI between EES and bare-metal stent (BMS) by using optical coherence tomography (OCT). ..................................................................................................................................................................................... Methods A prospective OCT examination was performed in 102 patients at 10 months after stent implantation for treatment of and results STEMI. A total of 1253 frames with 12 772 struts in 61 EESs and 776 frames with 8594 struts in 41 BMSs were analysed. There were no significant differences in the percentage of uncovered struts (2.1 + 2.8 vs. 1.7 + 2.7%, P ¼ 0.422) and malapposed struts (0.7 + 1.3 vs. 0.6 + 1.2%, P ¼ 0.756) between EES and BMS. The frequency of intra-stent thrombus was comparable between the two stents (13 vs. 10%, P ¼ 0.758). The mean neointimal thickness was smaller in EES compared with BMS (104 + 39 vs. 388 + 148 mm, P , 0.001). In-segment binary restenosis and target lesion revascularization was less often seen in EES compared with BMS (3 vs. 17%, P ¼ 0.028 and 2 vs. 12%, P ¼ 0.037, respectively). ..................................................................................................................................................................................... Conclusion When compared with BMS, EES showed a lower rate of stent restenosis, similar frequency of neointimal coverage, stent malapposition, and intra-stent thrombus at 10 months after stent implantation in STEMI. Our results suggest the safety and effectiveness of EES in primary percutaneous coronary intervention for STEMI patients.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Everolimus-eluting stent † ST-segment elevation myocardial infarction † Stent malapposition † Optical coherence tomography
Introduction The safety and efficacy of bare-metal stents (BMS) have been established in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).1,2 The first-generation drug-eluting stents (DES) have dramatically reduced in-stent restenosis (ISR) and target lesion
revascularization (TLR) after primary PCI in comparison with BMS.3 – 5 However, concerns have been raised regarding the longterm safety of DES in STEMI. Pathological studies reported that the implantation of first-generation DES in unstable coronary lesions might delay arterial healing and impair stent endothelialization.6 – 8 In addition, an optical coherence tomography (OCT) study at 13 months after primary PCI for STEMI demonstrated
* Corresponding author. Tel: +81 73 441 0621; fax: +81 73 446 0631, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
Downloaded from by guest on May 21, 2015
Received 24 May 2014; accepted after revision 27 October 2014; online publish-ahead-of-print 26 November 2014
514 that first-generation DES had a higher rate of uncovered struts with neointima and incomplete stent apposition in comparison with BMS.9 Recently, second-generation DES, such as the everolimuseluting stent (EES), have been developed to improve the safety profile by means of more biocompatible polymers, reduced drug dose with adapted release kinetics, and reduced strut thickness.10 Some clinical trials have demonstrated the superior efficacy of EES in STEMI compared with BMS and first-generation DES.11 – 13 We therefore evaluated the late vascular response and long-term safety of second-generation EES in STEMI when compared with BMS by using OCT.
Methods
Y. Ino et al.
OCT image acquisition Patients were administered intravenous heparin (5000 IU) and intracoronary isosorbide dinitrate (2 mg) prior to the OCT procedure. Frequency-domain (FD)-OCT imaging system (C7-XRTM , St. Jude Medical, St. Paul, MN, USA) was used in the present study. Following a Z-offset adjustment, an FD-OCT image catheter (DragonflyTM imaging catheter, St Jude Medical, St Paul, MN, USA) was advanced distally to the stented segment over a 0.014-inch conventional angioplasty guidewire. After the catheter placement, preheated contrast media at 378C (OmnipaqueTM 350 Injection, Daiichi Pharmaceutical, Tokyo, Japan) was flushed through the guiding catheter at a rate of 2 – 4 mL/s for 3 – 6 s using an injector pump (Mark V; Medrad, PA, USA). When a blood-free image was observed, the FD-OCT imaging core was withdrawn up to 50 mm at a rate of 20 mm/s using the stand-alone electronic control of the pullback motor. FD-OCT images were stored digitally for subsequent analysis.
Study design
Coronary angiography Coronary angiography was carried out in the standard manner. Quantitative coronary angiographic analysis was performed using a validated automated edge detection algorithm (CAAS-5, Pie Medical, Maastricht, Netherlands) by experienced investigators (T.T. or Y.S.) who were blinded to the clinical information and OCT findings. The reference vessel diameter, minimal luminal diameter (MLD) of the lesion, and per cent diameter stenosis were measured in the view that was the most severe and not foreshortened. Acute gain was defined as the difference between the post-procedure MLD and the pre-procedure MLD. In-stent late loss was defined as the difference between the in-stent MLD at post-stenting and at follow-up. In-segment binary restenosis was defined as a percent diameter stenosis .50% in the stented segment plus the margins 5 mm proximal and distal to the stent at follow-up.
OCT analysis All OCT images were analysed by experienced investigators (K.S. or L.Y.) who were blinded to the clinical information and angiographic findings. FD-OCT analysis was performed using a dedicated off-line review system with semi-automated contour-detection software (St Jude Medical, St Paul, MN, USA). The Z-offset was adjusted again before FD-OCT analysis. All cross-sectional images (frames) were initially screened to assess quality. Inadequate images, including poor quality caused by residual blood or artefact, and bifurcations of side branches were excluded from the analyses.14 – 16 Stent-overlap segments were also excluded because of incorrect traces of the outer stent due to the limited penetration depth of OCT images and backscattering by the inner stent struts. Qualitative imaging assessment was performed at every frame to detect the presence of intra-stent thrombus. Because the distinction between fibrin clots and neointimal hyperplasia after DES implantation is sometimes impossible, only masses protruding through the stent struts into the lumen with OCT-signal backscattering and attenuation were defined as intra-stent thrombus.9,14 – 16 In order to avoid misclassification of small image artefacts, only protruding masses .250 mm diameter were included.9 Quantitative strut-level analysis was performed at 1 mm intervals along the entire stented segment. Neointimal coverage was assessed on each individual strut. If neointimal coverage of the strut was observed, neointimal thickness on each strut was measured from the neointimal surface to the centre of the strut blooming. An uncovered strut was defined as a strut with a measured neointimal thickness equal to 0 mm. A malapposed strut was defined as a strut with a distance between the centre of the strut blooming and the adjacent lumen border ≥110 mm in both EES and BMS. This criterion was determined by adding the actual strut thickness and polymer thickness to the OCT resolution limit (EES: 81 + 7.8 + 20 ¼ 108.8 mm; BMS: 81 + 20 ¼ 101 mm). The maximum length of the segment with uncovered struts (or malapposed struts) was estimated as [the number of cross-sections with uncovered struts (or malapposed struts)] × [longitudinal interval between the analysed cross-sections (1 mm)]. Each stent strut condition was classified into one of the four categories (Figure 1):9,16 (a) well apposed to the vessel wall with neointimal coverage on the strut; covered and apposed strut, (b) incompletely apposed to the vessel wall with neointimal coverage; covered and malapposed strut, (c) well apposed to the vessel wall without neointimal coverage; uncovered and apposed strut, and (d) incompletely apposed to the vessel wall without neointimal coverage; uncovered and malapposed strut. Intra- and interobserver variability for the stent strut condition were assessed in the randomly selected 10
Downloaded from by guest on May 21, 2015
The inclusion criteria in the present study were admission to our hospital within 12 h from the onset of the symptom, a diagnosis of STEMI, and requiring primary PCI for a de novo culprit lesion in a native coronary artery. The clinical diagnosis of STEMI was based on the concurrence of all three following criteria: (i) continuous chest pain for at least 30 min, (ii) ST-segment elevation ≥0.1 mV in two or more contiguous leads on a 12-lead electrocardiogram, (iii) elevated myocardial enzymes [serum creatine kinase-MB (myocardial band) fraction levels more than two times higher than normal]. Exclusion criteria were left main disease, ostial right coronary artery lesions, renal insufficiency with baseline serum creatinine .2.0 mg/dL, the age younger than 20 years, cardiogenic shock, and inability to comply with dual-antiplatelet therapy and follow-up requirements. This was a prospective, open-label, non-randomized, single-centre study in Wakayama Medical University. The study had two periods. In the first period (between January 2011 and July 2011), patients with STEMI requiring primary PCI were assigned to Multilink Vision BMS (Abbott Vascular, Santa Clara, CA, USA) implantation. In the second period (between August 2011 and January 2012), patients with STEMI requiring primary PCI were assigned to Xience V EES (Abbott Vascular, Santa Clara, CA, USA) implantation. Angiographic and OCT follow-up was scheduled at 10 months after primary PCI to compare the late vascular response after stent implantation in STEMI between EES and BMS. All patients received dual-antiplatelet therapy with aspirin (100 mg/day) and clopidogrel (75 mg/day) for 12 months after primary PCI. The study protocol was approved by the Wakayama Medical University Ethics Committee, and all patients provided informed consent before participation.
515
Vascular response of EES and BMS in STEMI
Figure 1 Each stent strut condition. Each stent strut condition was classified as covered and apposed strut (A), covered and malapposed strut (B), uncovered and apposed strut (C), and uncovered and malapposed strut (D).
Statistical analysis Statistical analysis was performed with Stat View 5.0J (SAS Institute, Cary, NC, USA). Categorical variables were presented as frequencies, with comparison using x2 statistics or Fisher’s exact test (if the expected cell value was ,5). Normally distributed continuous variables were presented as mean + SD and were compared using unpaired Student’s t-tests; non-normally distributed continuous variables were presented as median (interquartile range) and were compared with the Mann– Whitney U test. A P-value of ,0.05 was considered statistically significant.
Results Baseline clinical characteristics Primary PCI was performed in 133 patients with STEMI during the study period (53 patients in the first period and 80 patients in the second period). Of these, we released 18 patients (7 and 11 patients) according to the exclusion criteria. Furthermore, we excluded nine patients (three and six patients) due to refusal of the scheduled followup angiography, two patients with non-cardiac death (EES ¼ 1 and BMS ¼ 1), and two patients (EES ¼ 1 and BMS ¼ 1) with subacute stent thrombosis. These subacute stent thrombosis events occurred at 12 and 9 days after stent implantation and caused non-fatal myocardial reinfarction. Thus, 102 patients (EES ¼ 61 and BMS ¼ 41) were assessed in the present study. Patient clinical characteristics are shown in Table 1. Age, gender, coronary risk factors, and peak levels of cardiac enzymes were similar between EES and BMS. The median time from stent implantation to follow-up OCT imaging in EES and BMS was 10.0 months
Table 1
Patient clinical characteristics EES (n 5 61)
BMS (n 5 41)
P-value
Age (years)
67 + 11
65 + 9
0.256
Male, n (%) Coronary risk factors
46 (75)
34 (83)
0.366
Hypertension, n (%)
49 (80)
31 (76)
0.570
Dyslipidaemia, n (%) Diabetes mellitus, n (%)
46 (75) 22 (36)
30 (73) 14 (34)
0.799 0.842
Cigarette smoking, n (%)
34 (56)
27 (66)
0.307
................................................................................
Cardiac enzyme at baseline Peak creatinine kinase 3115 + 1880 3347 + 2286 (IU/L) Peak creatinine kinase MB 313 + 170 338 + 269 (IU/L) Medications at follow-up
0.577 0.557
Aspirin, n (%)
61 (100)
41 (100)
1.000
Thienopiridine, n (%) Statin, n (%)
59 (97) 52 (85)
39 (95) 37 (90)
0.999 0.551
ACEI/ARB, n (%)
53 (87)
38 (93)
0.518
Calcium antagonist, n (%) 17 (28) b-Blocker, n (%) 37 (61)
9 (22) 28 (68)
0.501 0.432
Total cholesterol (mg/dL) 161 + 29 LDL-cholesterol (mg/dL) 88 + 24
156 + 30 82 + 21
0.486 0.182
HDL-cholesterol (mg/dL) 43 + 11
Laboratory data at follow-up
44 + 12
0.741
138 + 85 116 + 31
145 + 99 122 + 43
0.665 0.441
HbA1C (%)
6.2 + 1.5
6.4 + 1.7
0.421
hs-CRP (mg/L)
0.9 + 0.7
0.1 + 0.1
0.180
Triglyceride (mg/dL) Fasting glucose (mg/dL)
Values are given as n (%) or mean + standard deviation. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BMS, bare-metal stent; EES, everolimus-eluting stent; HDL, high-density lipoprotein; hs-CRP, high-sensitive C-reactive protein; LDL, low-density lipoprotein; MB, myocardial band.
(9.5 and 10.5) and 10.0 months (9.3 and 10.8), respectively (P ¼ 0.925). The medications and laboratory data at follow-up were not different between the two groups.
Downloaded from by guest on May 21, 2015
stent-treated lesions (EES ¼ 5 and BMS ¼ 5) and showed excellent concordance (k ¼ 0.92 and 0.90, respectively). 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 within the stent. The volume was calculated with the use of Simpson’s rule. Reproducibility of neointimal thickness and volume measurement was assessed in the randomly selected 10 stent-treated lesion (EES ¼ 5 and BMS ¼ 5). There was a good correlation for the repeated measurements by the same observer (r ¼ 0.991 and 0.987, respectively) and two different observers (r ¼ 0.992 and 0.989, respectively).
516
Y. Ino et al.
Angiographic and procedural characteristics Angiographic findings and procedural characteristics are shown in Table 2. Angiographic findings at pre-intervention were similar between the two groups. Stent diameter was smaller (3.17 + 0.34 vs. 3.49 + 0.34 mm, P , 0.001) and stent length was longer (22 + 6 vs. 19 + 4 mm, P ¼ 0.004) in EES compared with BMS. Although MLD at post-intervention was smaller in EES, MLD at follow-up was significantly greater in EES compared with BMS (2.86 + 0.57 vs. 2.16 + 0.77 mm, P , 0.001). Percent diameter stenosis at
Table 2 Angiographic findings and procedural characteristics BMS (n 5 41)
P-value
LAD/LCX/RCA TIMI flow grade 0/1/2/3
32/8/21 33/8/11/9
20/5/16 25/2/10/4
0.894 0.413
Ulceration
14 (23)
9 (22)
0.999
Thrombus Reference vessel diameter (mm) Minimum lumen diameter (mm) Percent diameter stenosis (%) Lesion length (mm)
44 (72) 3.10 + 0.46
31 (76) 3.23 + 0.38
0.696 0.156
0.18 + 0.24
0.15 + 0.28
0.575
94 + 8
96 + 8
0.247
16 + 8
15 + 5
0.431
Stent diameter (mm) Stent length (mm)
3.17 + 0.34 22 + 6
3.49 + 0.34 19 + 4
................................................................................ Pre-intervention
Stents and procedures ,0.001 0.004
Stent to artery ratio
1.05 + 0.08
1.08 + 0.12
0.111
Maximal pressure (atm) Thrombectomy, n (%)
16 + 4 47 (77)
16 + 4 32 (78)
0.299 0.906
Direct stenting, n (%)
10 (16)
6 (15)
0.811
Onset to balloon time (min)
278 + 125
289 + 149
0.679
Minimum lumen diameter (mm)
3.01 + 0.41
3.27 + 0.38
0.002
Percent diameter stenosis (%)
4+4
5+3
0.111
OCT findings The follow-up OCT examination was successfully performed in all patients. Of all recorded frames in the stent-treated lesion, 2.2% in EES and 2.4% in BMS (P ¼ 0.756) were excluded from the analysis due to inadequate images, bifurcations, or stent overlapping segments. We analysed a total of 1253 frames with 12 772 struts in EES and 776 frames with 8594 struts in BMS. Frequency distribution of neointimal thickness on stent struts is shown in Figure 2. Approximately 98% of struts were covered by neointima in both EES and BMS. The median neointimal thickness was significantly smaller in EES compared with BMS (80 mm (50 and 130) vs. 350 mm (190 and 540), P , 0.001). The OCT findings at 10-month follow-up are shown in Table 3. In the stent-treated lesion-level analysis, the stent strut conditions, such as percentage of uncovered struts and malapposed struts, were not different between EES and BMS. The frequency of lesions with any uncovered struts (49 vs. 34%, P ¼ 0.133) and the maximum length of segments with uncovered struts (P ¼ 0.151) were similar between the two stents. The frequency of lesions with any malapposed struts (34 vs. 22%, P ¼ 0.175) and the maximum length of segments with malapposed struts (P ¼ 0.215) were also comparable between the two stents. Furthermore, the frequency of intra-stent thrombus was not different between EES and BMS (13 vs. 10%, P ¼ 0.758). In the morphometric analysis, although the minimum stent area was smaller (P ¼ 0.003) in EES, the minimum lumen area was larger (P , 0.001), and the maximum neointimal area was smaller (P , 0.001) in EES compared with BMS. There was no difference in the maximum malapposition area and the malapposition volume between EES and BMS. Representative OCT images of EES and BMS are shown in Figures 3 and 4, respectively.
Post-intervention
10-month follow-up Minimum lumen diameter (mm) Percent diameter stenosis (%) In-stent late loss (mm) In-segment binary restenosis, n (%) Target lesion revascularization, n (%)
Discussion Healing delay after DES
2.86 + 0.57
2.16 + 0.77
,0.001
8 + 10
38 + 22
,0.001 ,0.001
0.15 + 0.38
1.11 + 0.68
2 (3)
7 (17)
0.028
1 (2)
5 (12)
0.037
Values are given as n (%) or mean + standard deviation. BMS, bare-metal stent; EES, everolimus-eluting stent; LAD, left anterior descending; LCX, left circumflex; RCA, right coronary artery; TIMI, Thrombolysis In Myocardial Infarction.
First-generation DES has dramatically reduced ISR and TLR after primary PCI for STEMI in comparison with BMS.3 – 5 Nevertheless, concerns have been raised regarding the long-term safety after DES in STEMI. Pathological studies reported that first-generation DES implantation in unstable coronary lesions might delay arterial healing and impair stent endothelialization.6 – 8 Because sirolimus and paclitaxel are highly lipophilic, it is likely that these agents have high affinity for lipid-rich plaques, dwell there for long periods of time, and influence healing by retarding smooth muscle cell proliferation and endothelial regrowth. In addition, the lipid-rich necrotic cores are more avascular compared with the fibrous dominant plaques and have fewer cells. Therefore, these areas might be less likely to be covered by migrating and proliferating cells from adjacent areas. Finn et al. demonstrated that a ratio of uncovered to total stent
Downloaded from by guest on May 21, 2015
EES (n 5 61)
follow-up (8 + 10 vs. 38 + 22%, P , 0.001) and in-stent late loss (0.15 + 0.38 vs. 1.11 + 0.68 mm, P , 0.001) were significantly smaller in EES compared with BMS. In-segment binary restenosis was observed in two cases in EES and seven cases in BMS (3 vs. 17%, P ¼ 0.028). Target lesion revascularization was performed in one case in EES and five cases in BMS (2 vs. 12%, P ¼ 0.037). There was no case with late-stent thrombosis in the present study.
517
Vascular response of EES and BMS in STEMI
Figure 2 The frequency distributions of the neointimal thickness at intervals of 50 mm. Struts with a neointimal thickness of 60– 100 mm were most frequently observed in EES, whereas the neointimal thickness in BMS was widely distributed. BMS, bare-metal stent; EES, everolimus-eluting stent.
Table 3
OCT findings at 10-month follow-up BMS (n 5 41)
P-value
Stent-treated lesion-level analysis Stent strut condition Uncovered struts (%)
2.1 + 2.8
1.7 + 2.7
0.422
Malapposed struts (%) Covered and apposed struts (%)
0.7 + 1.3 97.8 + 3.0
0.6 + 1.2 98.4 + 2.7
0.756 0.366
Covered and malapposed struts (%)
0.1 + 0.2
0.1 + 0.3
0.947
Uncovered and apposed struts (%) Uncovered and malapposed struts (%)
1.6 + 2.3 0.6 + 1.2
1.2 + 2.0 0.4 + 0.9
0.379 0.596
Lesion with any uncovered struts, n (%)
30 (49)
14 (34)
0.133
Maximum length of segment with uncovered struts (mm) Lesion with any malapposed struts, n (%)
0.9 + 1.3 21 (34)
0.6 + 0.8 9 (22)
0.151 0.175
0.5 + 0.8
0.3 + 0.6
0.215
8 (13)
4 (10)
0.758
Maximum length of segments with malapposed struts (mm) Intra-stent thrombus, n (%) Morphometric analysis Minimum stent area (mm2)
6.57 + 1.95
7.74 + 1.79
0.003
Maximum neointimal area (mm2) Minimum lumen area (mm2)
1.83 + 0.99 5.61 + 1.91
5.49 + 1.84 3.60 + 1.85
,0.001 ,0.001
Maximum malapposition area (mm2)
0.11 + 0.26
0.13 + 0.32
Stent volume (mm3) Neointimal volume (mm3)
158.78 + 51.54 19.10 + 11.82
175.78 + 65.66 71.60 + 43.37
0.147 ,0.001
Lumen volume (mm3)
139.47 + 48.59
104.17 + 41.68
,0.001
Malapposition volume (mm3)
0.19 + 0.42
0.18 + 0.43
0.688
0.925
Values are given as n (%) or mean + standard deviation. BMS, bare-metal stent; EES, everolimus-eluting stent; OCT, optical coherence tomography.
struts per section .30% was the most powerful predictor of stent thrombosis.8 The efficacy of first-generation DES use in primary PCI for STEMI may be offset by an increased risk of stent thrombosis and accompanying clinical outcomes due to delayed arterial healing.
Second-generation DES Second-generation EES has been developed to improve the safety and efficacy of coronary stents by modifying the eluted drug, drug carrying system, and stent design.10,12 EES is a cobalt chromium
Downloaded from by guest on May 21, 2015
EES (n 5 61)
...............................................................................................................................................................................
518
Y. Ino et al.
alloy stent with thin (81 mm) strut thickness, which is coated with a thin (7.8 mm), non-adhesive, durable, biocompatible fluorinated copolymer releasing a reduced dose of everolimus compared with the dose used in first-generation DES. Therefore, EES implantation may introduce a more favourable vascular response. Furthermore, the EES uses a fluorinated copolymer, which comprises vinylidene fluoride and hexafluoropropylene monomers that might confer a certain degree of thromboresistance and haemocompatibility.17 This benefit of low thrombogenicity of EES may even be extended to uncovered and/or malapposed stent struts.
EES in AMI Previous clinical studies and meta-analyses reported that firstgeneration DES in primary PCI for STEMI increased the risk of very late stent thrombosis despite a reduction in target vessel revascularization.18,19 The OCT sub-study of the HORIZONS-AMI trial showed that implantation of the first-generation paclitaxel-eluting stent in AMI significantly reduced neointimal hyperplasia, but resulted in higher rates of uncovered and malapposed stent struts at 13-month follow-up in comparison with BMS.9 Recently, the XAMI trial demonstrated that second-generation EES was superior to SES
for major adverse cardiac event-free survival at 1 year in patients with AMI.11 The EXAMINATION trial indicated that EES in STEMI reduced not only TLR, but also stent thrombosis in comparison with BMS.12 A recent OCT study has demonstrated that EES when compared with first-generation DES has more favourable late vascular response in stable coronary artery disease.20 In AMI, however, an OCT study assessing the late vascular response and long-term safety after EES has been lacking. The present OCT study demonstrated that the extent of neointimal coverage after EES in STEMI was similar to that after BMS. In addition, the incidence of uncovered struts, malapposed struts, and intra-stent thrombus after EES in the present study was lower than that after first-generation DES reported in the previous OCT studies.9,21 This favourable vascular response after EES was thought to be owing to low drug dose, biocompatibility of polymers, and the fluorinated copolymer. Our data support the favourable results of the recent clinical trials of EES for STEMI, suggesting safety and efficacy of EES for primary PCI in STEMI patients. On the other hand, even if 98% of all struts were covered in both EES and BMS at follow-up, and lesions with any uncovered struts did not differ between EES and BMS (49 and 34%), it cannot be excluded a
Downloaded from by guest on May 21, 2015
Figure 3 Representative OCT images of EES at 10-month follow-up. Angiography showed no intra-stent restenosis in the right coronary artery (A, arrow). Cross-sectional OCT images visualized well apposed struts with neointimal coverage (B – D). EES, everolimus-eluting stent; OCT, optical coherence tomography.
Vascular response of EES and BMS in STEMI
519
possible clustering distribution of non-coverage strut, for example: some particular concentration of uncovered struts in some patients or in some regions within stent. Moreover, it has to be considered that also individual, mechanical, and loco-regional factors (levels of circulating endothelial progenitor cells or regional shear stress) can play a role in neointimal healing and the only differences in percentage coverage cannot be always advocated to explain the clinical results regarding stent thrombosis.22
Study limitations The present study has several limitations. First, the major limitation of the present study is the suboptimal simplified statistical analysis of such a complex OCT dataset. The applied analyses are inappropriate for clustered data and the results should be considered just as an approximation. Second, this is a non-randomized, single-centre study with a relatively small study population, which may cause selection bias. The decision of stent diameter and length was left to the operator, and this might have played a role in the difference in size of EES with respect to BMS. In fact, although reference vessel size was similar, EES was smaller and longer compared with BMS. In several
studies, small vessels and small stents show better coverage than large vessels and large stents. The stent size in EES might contribute the better coverage partially. Third, some cross-sections were excluded from the OCT analysis. However, those were only 2.2% in EES and 2.4% in BMS of all recorded frames (P ¼ 0.756). Fourth, in this study, a single criterion of malapposition in both EES and BMS has been chosen. Therefore, in BMS (without polymer thickness), malappositions might have been underestimated with respect to EES. However, the difference was small (only 7.8 mm) and under the OCT resolution limit. Fifth, endothelial cell dimensions are below the resolution of OCT. Some struts appearing bare may have been covered by endothelium, and thus, misclassified. Sixth, OCT data before and immediately after stent implantation were not available. Therefore, it was unclear whether the stent malapposition and intra-stent thrombus were persistent or late acquired. Finally, this study was not powered or not designed to assess the relationship between suboptimal stent results as determined by the follow-up OCT examination and future development of stent thrombosis. Further studies are required to investigate the clinical implications of OCT findings at 10 months after stent implantation.
Downloaded from by guest on May 21, 2015
Figure 4 Representative OCT images of BMS at 10-month follow-up. Angiography showed in-stent restenosis in the mid portion of right coronary artery (A, arrow). Cross-sectional OCT images visualized thick neointima in the stented segment (B – D). BMS, bare-metal stent; OCT, optical coherence tomography.
520
Y. Ino et al.
Conclusions When compared with BMS, EES showed a lower rate of stent restenosis and similar frequency of neointimal stent coverage, stent malapposition, and intra-stent thrombus at 10 months after stent implantation for treatment of STEMI. Our results suggest the safety and effectiveness of EES in primary PCI for STEMI patients.
12.
13.
Conflict of interest: none declared.
References
14. 15.
16. 17.
18.
19.
20.
21.
22.
Downloaded from by guest on May 21, 2015
1. Grines CL, Cox DA, Stone GW, Garcia E, Mattos LA, Giambartolomei A et al. Coronary angioplasty with or without stent implantation for acute myocardial infarction. Stent Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 1999; 341:1949 –56. 2. De Luca G, Suryapranata H, Stone GW, Antoniucci D, Biondi-Zoccai G, Kastrati A et al. Coronary stenting versus balloon angioplasty for acute myocardial infarction: a meta-regression analysis of randomized trials. Int J Cardiol 2008;126:37 –44. 3. Spaulding C, Henry P, Teiger E, Beatt K, Bramucci E, Carrie´ D et al. Sirolimus-eluting versus uncoated stents in acute myocardial infarction. N Engl J Med 2006;355: 1093 –104. 4. Stone GW, Lansky AJ, Pocock SJ, Gersh BJ, Dangas G, Wong CS et al. Paclitaxeleluting stents versus bare-metal stents in acute myocardial infarction. N Engl J Med 2009;360:1946 – 59. 5. Kastrati A, Dibra A, Spaulding C, Laarman GJ, Menichelli M, Valgimigli M et al. Meta-analysis of randomized trials on drug-eluting stents vs. bare-metal stents in patients with acute myocardial infarction. Eur Heart J 2007;28:2706 –13. 6. Nakazawa G, Finn AV, Joner M, Ladich E, Kutys R, Mont EK et al. 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. 7. Finn AV, Nakazawa G, Ladich E, Kolodgie FD, Virmani R. Does underlying plaque morphology play a role in vessel healing after drug eluting stent implantation? JACC Cardiovasc Imaging 2008;1:485 –8. 8. Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 2007;115:2435 – 41. 9. Guagliumi G, Costa MA, Sirbu V, Musumeci G, Bezerra HG, Suzuki N et al. Strut coverage and late malapposition with paclitaxel-eluting stents compared with bare metal stents in acute myocardial infarction: optical coherence tomography substudy of the HORIZONS-AMI Trial. Circulation 2011;123:274 –81. 10. Palmerini T, Kirtane AJ, Serruys PW, Smits PC, Kedhi E, Kereiakes D et al. Stent thrombosis with everolimus-eluting stents: meta-analysis of comparative randomized controlled trials. Circ Cardiovasc Interv 2012;5:357 –64. 11. Hofma SH, Brouwer J, Velders MA, van’t Hof AW, Smits PC, Quere´ M et al. Secondgeneration everolimus-eluting stents versus first-generation sirolimus-eluting stents
in acute myocardial infarction: 1-year results of the randomized XAMI (XienceV Stent vs. Cypher Stent in Primary PCI for Acute Myocardial Infarction) trial. J Am Coll Cardiol 2012;60:381 –7. Sabate M, Cequier A, In˜iguez A, Serra A, Hernandez-Antolin R, Mainar V et al. Everolimus-eluting stent versus bare-metal stent in ST-segment elevation myocardial infarction (EXAMINATION): 1 year results of a randomised controlled trial. Lancet 2012;380:1482 –90. Bangalore S, Amoroso N, Fusaro M, Kumar S, Feit F. Outcomes with various drug-eluting or bare metal stents in patients with ST-segment –elevation myocardial infarction: a mixed treatment comparison analysis of trial level data from 34068 patient-years of follow-up from randomized trials. Circ Cardiovasc Interv 2013;6: 378 –90. Kubo T, Akasaka T. Optical coherence tomography imaging: current status and future perspectives. Cardiovasc Interv Ther 2010;25:2 –10. Park J, Shin DH, Kim BK, Her AY, Kim YH, Choi HH et al. Relationship between aspirin/clopidogrel resistance and intra-stent thrombi assessed by follow-up optical coherence tomography after drug-eluting stent implantation. Eur Heart J Cardiovasc Imaging 2013;14:1181 – 6. Lowe HC, Narula J, Fujimoto JG, Jang IK. Intracoronary optical diagnostics current status, limitations, and potential. JACC Cardiovasc Interv 2011;4:1257 –70. Kolandaivelu K, Swaminathan R, Gibson WJ, Kolachalama VB, Nguyen-Ehrenreich KL, Giddings VL et al. Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation 2011;123:1400 –9. Kalesan B, Pilgrim T, Heinimann K, Ra¨ber L, Stefanini GG, Valgimigli M et al. Comparison of drug-eluting stents with bare metal stents in patients with ST-segment elevation myocardial infarction. Eur Heart J 2012;33:977 –87. Jensen LO, Maeng M, Thayssen P, Kaltoft A, Tilsted HH, Bøttcher M et al. Clinical outcome after primary percutaneous coronary intervention with drug-eluting and bare metal stents in patients with ST-segment elevation myocardial infarction. Circ Cardiovasc Interv 2008;1:176 – 84. Toledano Delgado FJ, Alvarez-Ossorio MP, de Lezo Cruz-Conde JS, Bellido FM, Romero Moreno MA, Ferna´ndez-Aceytuno AM et al. Optical coherence tomography evaluation of late strut coverage patterns between first-generation drug-eluting stents and everolimus-eluting stent. Catheter Cardiovasc Interv 2013; doi:10.1002/ccd.25235. Gonzalo N, Barlis P, Serruys PW, Garcia-Garcia HM, Onuma Y, Ligtheart J et al. Incomplete stent apposition and delayed tissue coverage are more frequent in drug-eluting stents implanted during primary percutaneous coronary interventions for ST-segment elevation myocardial infarction then in drug-eluting stents implanted for stable/unstable angina: insights from optical coherence tomography. JACC Cardiovasc Interv 2009;2:445–52. Gutie´rrez-Chico JL, van Geuns RJ, Regar E, van der Giessen WJ, Kelbæk H, Saunama¨ki K et al. Tissue coverage of a hydrophilic polymer-coated zotarolimuseluting stent vs. a fluoropolymer-coated everolimus-eluting stent at 13-month follow-up: an optical coherence tomography substudy from the RESOLUTE All Comers trial. Eur Heart J 2011;32:2454 –63.
