Vascular Responses in Patients With and Without Diabetes Mellitus After Everolimus-Eluting Stent Implantation

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1 2188 IWASAKI M et al. Circulation Journal ORIGINAL ARTICLE Official Journal of the Japanese Circulation Society Cardiovascular Intervention Vascular Responses in Patients With and Without Diabetes Mellitus After Everolimus-Eluting Stent Implantation Optical Coherence Tomography Study Masamichi Iwasaki, MD; Hiromasa Otake, MD; Toshiro Shinke, MD; Masayuki Nakagawa, MD; Hirotoshi Hariki, MD; Tsuyoshi Osue, MD; Takumi Inoue, MD; Yu Taniguchi, MD; Ryo Nishio, MD; Hiroto Kinutani, MD; Akihide Konishi, MD; Noritoshi Hiranuma, MD; Masaru Kuroda, MD; Junya Shite, MD; Ken-ichi Hirata, MD Background: Previous reports have shown potential disadvantages of limus-derivative drugs for the stenting treatment of patients with diabetes mellitus (DM). Methods and Results: We studied 159 coronary artery lesions (DM: n=72, non-dm: n=87) in 123 patients treated with everolimus-eluting stent (EES) and who underwent scheduled 9-month follow-up angiography with optical coherence tomography (OCT) regardless of symptoms. In addition to standard OCT variables, neointimal unevenness score (maximum/average neointimal thickness) and stent eccentricity index (minimum/maximum stent diameter) were calculated for each cross-section. To investigate a potential baseline difference between DM and non-dm lesions, pre- and post-interventional intravascular ultrasound (IVUS) images were also evaluated as an IVUS subgroup analysis. The average neointimal thickness and neointimal coverage did not differ between DM and non-dm patients. DM patients had, however, greater asymmetric stent expansion and variability of neointimal thickness than non-dm patients. There was a weak, but significant association between average stent eccentricity index and neointimal unevenness score. The IVUS substudy showed that the culprit plaque volume and plaque eccentricity in DM patients were significantly greater than in non-dm patients. Conclusions: Although EES provided a similar level of average neointimal thickness and coverage both in the presence and absence of DM, uneven neointimal suppression occurred in DM patients. A larger plaque volume of the culprit lesion may hamper symmetric stent expansion, possibly explaining the non-uniform neointimal suppression in DM patients. (Circ J 2014; 78: ) Key Words: Everolimus-eluting stents; Diabetes mellitus; Optical coherence tomography Patients with diabetes mellitus (DM) are at a particularly high risk for restenosis and target lesion revascularization (TLR) than those without. 1 3 The primary mechanism for this increased risk of restenosis may be the occurrence of diffuse and accelerated neointimal proliferation within the stented segment. 4,5 Although the introduction of the first-generation drug-eluting stents (DES) has markedly reduced the number of cases of restenosis, DM is still associated with an increased risk of restenosis and unfavorable clinical outcomes. 2,3 Second-generation everolimus-eluting stents (EES) have recently been found to be superior to the first-generation paclitaxel-eluting stents in the reduction of the rates of TLR; 6,7 however, it remains controversial whether these significant improvements are affected by the presence or absence of DM. Therefore, this study aimed to determine the differences between the arterial responses to EES implantation in patients with DM and those without DM. Editorial p 2149 Methods Study Population and Protocol Between February 2010 and December 2011, 590 patients underwent elective percutaneous coronary intervention (PCI) and of them, those meeting the following inclusion criteria were considered as candidates for the study: (a) de novo native coronary lesion or in-stent restenosis (ISR >50% diameter stenosis) Received December 24, 2013; accepted May 21, 2014; released online July 14, 2014 Time for primary review: 22 days Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan Mailing address: Hiromasa Otake, MD, FACC, Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kusunoki-cho, Chuo-ku, Kobe , Japan. hotake@med.kobe-u.ac.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 OCT Study of EES in DM Patients 2189 Figure 1. Optical coherence tomography and intravascular ultrasound measurements. (A-1,A-2) First, lumen and stent contours were manually traced on the cross-sectional images at 1-mm intervals. Second, maximum and minimum lumen/stent diameters were measured manually. Neointimal thickness inside each everolimus-eluting stent strut was measured in each cross-section. (A-3) Representative image of a peri-strut low-intensity area (white arrows) (A-4) Representative image of an intrastent thrombus (yellow arrow). (B) Intravascular ultrasound cross-sectional image, duplicated to show the external elastic membrane as a red line, and the lumen by the yellow line. The maximum and minimum plaque plus media thicknesses are indicated by the radial green lines. The eccentricity index is calculated as the ratio of the maximum to minimum plaque plus media thicknesses. The maximum wall thickness measures 1.2 mm, minimum wall thickness measures 0.6 mm, and eccentricity index is calculated to be 2.0. PEI, plaque eccentricity index. treated with EES, (b) native vessel size of diameter mm, (c) stable angina or acute coronary syndrome (ACS), (d) anatomical suitability of the target artery for optical coherence tomography (OCT), and (e) written informed consent of the patient to undergo OCT. The exclusion criteria included the following: (a) ST-elevated and non-st-elevated myocardial infarction (MI), (b) contraindication for dual antiplatelet therapy, (c) left main coronary artery disease, (d) congestive heart failure, and (e) use of rotablator. Among the patients meeting the inclusion criteria, 317 were treated with EES and 214

3 2190 IWASAKI M et al. Statistical Analysis Statistical analysis was conducted using a commercially available software package (StatView ver. 5.0, MedCalc Software ver. 9.3, Mariakerke, Belgium). Continuous variables are presented as mean ± SD. Because multiple stenting in each case was performed with overlapping, statistical analysis was performed on a lesion basis. Differences in the continuous parameters between the 2 groups were calculated using an unpaired t-test. Categorical variables were presented using frequency counts, and intergroup comparisons were made using Fisher s exact test. Differences in continuous parameters among 3 groups (DM with insulin, DM without insulin, and non-dm) were calculated using a 1-way ANOVA. Simple correlations beof them (257 EES) underwent follow-up coronary angiography, irrespective of the presence or absence of symptoms, as is routine practice in Japan. The angiographic follow-up rate did not different between the DM and non-dm groups (DM with follow-up: n=100, without follow-up: n=51; non-dm with follow-up: n=114, without follow-up: n=52, P=0.207). Among these 214 patients, 89 were excluded because they had a followup duration <6 months or >12 months; 2 patients were excluded because of poor-quality OCT images. Finally, we selected 123 patients (159 lesions) who were scheduled to undergo a 9-month follow-up OCT analysis (Figure S1). DM was defined as a history of diabetes necessitating current treatment with insulin, oral agents, and/or dietary therapy. Patients were prescribed ticlopidine (200 mg/day) or clopidogrel (75 mg/day) for at least 1 year after stenting. The study protocol was approved by the ethics committee of Kobe University, and the study was carried out in accordance with the guidelines of the Declaration of Helsinki. All the enrolled study patients gave written informed consent to undergo the follow-up OCT and for enrollment into the study. Angiographic Analysis Cine angiograms were analyzed with a computer-assisted, automated edge-detection algorithm (CMS-Medis Medical Imaging Systems, Leiden, The Netherlands). Angiographic restenosis was defined as lesions with >50% diameter stenosis at followup angiography. To investigate the difference in residual plaque between lesions in DM and non-dm patients, the minimal lumen diameter (MLD) for each lesion within a distance of 5 mm distal or proximal from the stent edge was measured. OCT Examination OCT examination was performed using the time-domain M2 system (LightLab Imaging, Westford, MA, USA) as reported previously. 8 Briefly, a inch OCT catheter (ImageWire, LightLab Imaging) was advanced into the distal end of the stented lesion through an occlusion balloon catheter (HeliosTM, LightLab Imaging). The occlusion balloon was inflated to 0.6 atm, proximal to the culprit lesion, and lactated Ringer s solution was infused into the coronary artery from the distal tip of the occlusion balloon catheter at 0.5 ml/s. The entire length of the stent was imaged at 1 mm/s. Quantitative OCT Analysis All images were analyzed by independent observers who were blinded to the clinical presentations and lesion characteristics. Cross-sectional OCT images were analyzed at 1-mm intervals. Bifurcation lesions with major side branches were excluded from this analysis. Neointimal thickness inside each EES strut was measured. Stent area and maximum and minimum stent diameters were measured manually (Figures 1A-1,A-2). EES struts with neointimal thickness equal to 0 μm were defined as uncovered. A maximum distance >108 μm between the center reflection of the strut and adjacent vessel surface was defined as incomplete strut apposition. 9 To assess for stent asymmetric expansion, a stent eccentricity index (SEI) was determined by the minimum stent diameter divided by the maximum stent diameter in each cross-section. The average SEI was calculated for each stent. For the assessment of the unevenness of neointimal thickness, a neointimal unevenness score (NUS) was calculated for each cross-section as the maximum neointimal thickness in 1 crosssection divided by the average neointimal thickness of the cross-section. 10,11 Qualitative OCT Analysis As a factor in the qualitative OCT analysis, the peri-strut low-intensity area (PLIA), which is indicative of fibrin deposition or local inflammation, and the presence of thrombus were evaluated on follow-up OCT images. PLIA was defined as a region around stent struts that was homogenously hypointense to the surrounding tissue on the OCT images, without significant signal attenuation behind the area (Figure 1A-3). 10,12 To quantify the number of struts with PLIA (+), the incidence of +PLIA struts was calculated as the number of +PLIA struts divided by the number of all evaluated struts (%) for each +PLIA stent. Intracoronary thrombus was defined as a mass protruding beyond the stent strut into the lumen with significant attenuation behind the mass (Figure 1A-4) Because discrimination between red and white thrombus is not simple and not yet sufficiently sustained by validation studies, both types of thrombus (red and white) were included as intrastent thrombus. To differentiate thrombus from plaque protrusion or neointimal hyperplasia, we excluded protruding masses without significant signal attenuation and surface irregularity. Clinical Follow-up Major adverse cardiac events (MACE) were defined as a composite of death, MI, and target vessel revascularization (TVR), which was defined as any re-intervention (surgical or percutaneous) to treat a luminal stenosis occurring in the same coronary vessel treated at the index procedure, within and beyond the target-lesion limits. Long-term (ie, >9 months) clinical followup data were obtained from outpatient record reviews or telephone interviews. All patients were followed up for a minimum of 1 year (median=517 days) after the index procedure. Intravascular Ultrasound (IVUS) Substudy In order to further investigate the possible baseline differences between lesions in patients with and without DM, preprocedural IVUS images were evaluated for all the lesions, except those unavailable for IVUS examination because of chronic total occlusion, severe stenosis, severe tortuosity, and calcification. IVUS was performed in the standard fashion by using an automated motorized (1.0 mm/s) pullback with commercially available imaging systems (40-MHz IVUS catheter, Boston Scientific Corp, Natick, MA, or 20-MHz IVUS catheter, Volcano Corp, Rancho Cordova, CA, USA). Volumetric measurements were performed using planimetry software (EchoPlaque, Indec Systems Inc, Santa Clara, CA, USA), as described previously. 16 The percent plaque volume, plaque eccentricity index, and the number of lesions with >90-degree calcium arc were evaluated (Figure 1B). The plaque eccentricity index was determined as the ratio of the maximum to minimum plaque plus media thicknesses, and lesions with a plaque eccentricity index >3 were defined as eccentric plaques, in accordance with previous IVUS reports. 17,18 Further, we measured the maximum residual plaque area (uncovered plaque area) for each lesion within a distance of 5 mm distal or proximal from the stent edge.

4 OCT Study of EES in DM Patients 2191 Table 1. Characteristics of the Patients With and Without DM DM (n=57) Non-DM (n=66) P value Age (years) 65.6± ± Sex (male; n) 45 (78.9%) 47 (71.2%) Body mass index (kg/m 2 ) 24.7± ± Follow-up (days) 260.5± ± HT (n) 47 (82.5%) 47 (71.2%) Dyslipidemia (n) 43 (75.4%) 51 (77.3%) Smoker (n) 36 (63.2%) 34 (51.5%) Family history 12 (21.1%) 10 (15.2%) Dialysis 2 (3.5%) 1 (1.5%) Unstable angina (n) 9 (15.8%) 22 (33.3%) Use of statin (n) 47 (82.5%) 60 (90.9%) Use of clopidogrel (n) 55 (96.5%) 63 (95.5%) >0.999 Use of ACEI/ARB (n) 45 (79.3%) 43 (65.7%) Use of β-blocker (n) 32 (56.1%) 32 (48.5%) Use of PPI 43 (73.6%) 54 (81.3%) Treatment for DM Insulin 11 (19.3%) NA Oral drugs 39 (68.4%) NA Diet and exercise 7 (12.3%) NA HbA1c 6.70± ±0.60 <0.001 HDL-cholesterol 47.8± ± LDL-cholesterol 86.8± ± Triglycerides 139.6± ± Values are n (%) or mean SD. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; DM, diabetes mellitus; HDL, high-density lipoprotein; HT, hypertension; LDL, low-density lipoprotein; NA, not available; PPI, proton-pump inhibitor. tween the average SEI and average NUS were examined by Spearman s correlation. In order to investigate the baseline factors independently associated with asymmetric stent expansion and uneven neointimal proliferation, a multiple linear regression analysis was performed to explore the determinants of SEI and NUS in all cohorts. In patients who were enrolled in the IVUS substudy, we also performed linear regression analysis to see if there were direct relationships among baseline IVUS parameters and non-uniform neointimal suppression. Factors with a P value <0.10 in the univariate analysis were included in the multiple linear regression model. P 0.05 was considered statistically significant. Results The average interval to the follow-up OCT study was 265 days after stenting. The number of cases of ACS in the DM group was significantly lower than in the non-dm group. Otherwise, there were no significant differences between the 2 groups in the patient and lesion characteristics (Tables 1,2). Quantitative Coronary Angiography No intergroup differences were noted in baseline quantitative coronary angiographic findings (Table 2). The prevalence of calcification in the target lesion was significantly higher in DM patients than in non-dm patients (45.8% vs. 21.7%, P=0.007). At follow-up, the angiographic restenosis rate tended to be higher in the DM group than in the non-dm group (6.9% vs. 1.1%, P=0.09). The MLD of the region proximal to the stent after intervention was significantly smaller in the DM patients than in the non-dm patients (P=0.042). Further, the absence of DM was associated with a smaller MLD of both proximal and distal lesions at follow-up. Late loss in the stent-proximal and stent-distal regions was greater in DM patients than in non-dm patients (Table 2). Follow-up OCT Findings There was no significant difference between the 2 groups in the average neointimal thickness. The incidence of percent uncovered struts and percent malapposed struts showed no significant difference between patients with and without DM. However, lesions in the DM group showed a significantly smaller SEI (P<0.001). NUS was significantly greater for lesions in the DM group than for those in the non-dm group (Table 3). There was a weak, but significant, positive correlation between average SEI and NUS (Figure 2A). From the multivariable linear regression model that related prespecified baseline covariates to the SEI, baseline covariates independently associated with a higher risk of asymmetric stent expansion were DM, hypertension, and smoking (Table 4A). The multivariate analysis also showed that the presence of DM and hypertension was independent factors positively associated with uneven neointimal suppression after stent implantation (Table 4B). In this study, the proportions of lesions in DM patients with insulin, DM patients without insulin, and non-dm patients were 8.9%, 36.5%, and 54.7%, respectively. DM patients with insulin showed the greatest asymmetric stent expansion and uneven neointimal distribution followed by DM without insulin and non-dm lesions (ANOVA P=0.018 for NUS, ANOVA P=0.002 for SEI; Figures 2B,C). In the qualitative OCT analysis, subclinical thrombus attachment was identified in 14 patients (8.8%) in the overall population. Although not statistically significant, a tendency toward

5 2192 IWASAKI M et al. Table 2. Characteristics of the Lesion and Procedure in Patients With and Without DM DM (n=72) Non-DM (n=87) P value Target coronary artery Left anterior descending (n) Left circumflex (n) Right (n) ACC/AHA lesion type B2/C (n) 43 (59.7%) 47 (54.0%) De novo lesion (n) 59 (81.9%) 82 (94.3%) Chronic total occlusion (n) 11 (15.3%) 8 (9.2%) Bifurcation lesion (n) 16 (23.1%) 22 (28.6%) Calcification (n) 33 (45.8%) 25 (21.7%) Total number of stents (n) 1.2± ± Total stent length (mm) 23.6± ± Stent diameter (mm) 2.90± ± Maximum inflation pressure (atm) 14.1± ± Post-dilation (n) 44 (61.1%) 50 (57.5%) Quantitative content analysis In-stent analysis Pre-PCI Lesion length (mm) 18.7± ± Minimum diameter (mm) 0.68± ± Diameter stenosis (%) 67.2± ± Post-PCI Minimal diameter (mm) 2.48± ± Diameter stenosis (%) 9.8± ± Acute gain (mm) 1.80± ± Follow-up Minimum diameter (mm) 2.32± ± Diameter stenosis (%) 12.1± ± Restenosis (>50% of % diameter stenosis) 5 (6.9%) 1 (1.1%) Late loss (mm) 0.15± ± Proximal reference segment Post-PCI Minimum diameter (mm) 2.49± ± Follow-up Minimum diameter (mm) 2.34± ± Late loss at proximal segment (mm) 0.15± ± Distal reference segment Post-PCI Minimum diameter (mm) 2.18± ± Follow-up Minimum diameter (mm) 2.04± ± Late loss at distal segment (mm) 0.14± ±0.19 <0.001 Data are mean ± SD. ACC/AHA, American College of Cardiology/American Heart Association; DM, diabetes mellitus; PCI, percutaneous coronary intervention. a higher incidence of thrombus attachment was noted in DM patients compared with non-dm patients (P=0.054). The incidence of PLIA did not show any statistical difference between the 2 groups. Long-Term Clinical Follow-up No cases of death, MI or stent thrombosis occurred, but 8 patients in the DM group and 8 in the non-dm group required TLR. TLR events were noted in 3 patients in the DM group and 1 patient in the non-dm group. There was no significant difference in MACE during the follow-up period (Table 5). IVUS Substudy We performed pre-interventional IVUS of 58 lesions (DM: 30, non-dm: 28). The IVUS subgroup arm had larger MLD before PCI than the overall population. Otherwise, there was no difference in patient, lesion or procedural background between the IVUS subgroup and the overall population (Table S1). Pre-interventional plaque volume and post-interventional residual plaque area in DM patients were significantly greater than those in non-dm patients. In addition, lesions with a plaque eccentricity index >3 were more frequently observed in the DM group than in the non-dm group (Table 6). Regarding the relationships among baseline IVUS parameters and SEI or

6 OCT Study of EES in DM Patients 2193 Table 3. OCT Data and Analysis for Patients With and Without DM DM (n=72) Non-DM (n=87) P value Average number of struts (n) 220±98 197± Frequency of malapposed struts (%) 0.96± ± Frequency of uncovered struts (%) 1.17± ± Average neointimal thickness (μm) 100±43 104± Average neointimal area (mm 2 ) 0.73± ± Average NUS 1.87± ± Average SEI 0.89± ±0.03 <0.001 Minimum SEI 0.78± ± Percent peri-strut low-intensity area 3.68± ± Frequency of intracoronary thrombus (%) 10 (13.9%) 4 (4.6%) Values are n (%) or mean SD. DM, diabetes mellitus; NUS, neointima unevenness score; OCT, optical coherence tomography; SEI, stent eccentricity index. Figure 2. (A) Correlation between SEI and NUS. (B) Difference in the SEI among DM patients with insulin, DM patients without insulin, and non-dm patients, and (C) differences in the NUS among the same groups. DM, diabetes mellitus; NUS, neointimal unevenness score; SEI, stent eccentricity index. NUS, we found that SEI was significantly correlated with baseline plaque volume (r=0.417, P=0.038; Table S2). Also, NUS was significantly correlated with baseline plaque volume (r= 0.412, P=0.041) as well as the plaque eccentricity index (r= 0.287, P=0.041, Table S2). Discussion Neointimal Suppression in DM vs. Non-DM Patients In addition to small vessel size in DM patients, a more diffuse and accelerated form of atherosclerosis is considered to contribute to their increased risk of target vessel failure after bare metal stent placement. Currently, the use of DES has improved outcomes in the treatment of coronary artery disease across many patient populations, including DM patients. However, the effect of DM on the efficacy of EES remains unclear. Therefore in the present study, we compared the arterial responses to EES implantation in patients with and without DM by serial angiographic and OCT evaluation in a relatively large patient population.

7 2194 IWASAKI M et al. Table 4. Factors Correlated to (A) Stent Eccentricity Index and (B) Neointimal Unevenness Score Univariate Multivariate r P value r P value (A) Stent eccentricity index Sex DM HT Smoker (B) Neointimal unevenness score DM HT < DM, diabetes mellitus; HT, hypertension. Table 5. Clinical Events (Median 502 Days) in Patients With and Without DM DM (n=72) Non-DM (n=87) P value Major adverse cardiac events 8 (11.1%) 8 (9.2%) Cardiac death 0 (0%) 0 (0%) >0.999 Myocardial infarction 0 (0%) 0 (0%) >0.999 Definite/probable stent thrombosis 0 (0%) 0 (0%) >0.999 Target vessel revascularization 8 (11.1%) 8 (9.2%) Target lesion revascularization 3 (4.2%) 1 (1.1%) Values are n (%). DM, diabetes mellitus. Target vessel revascularization, any re-intervention (surgical or percutaneous) to treat a luminal stenosis occurring in the same coronary vessel treated at the index procedure. Table 6. IVUS Data and Analysis in Patients With and Without DM DM (n=30) Non-DM (n=28) P value Pre-interventional IVUS Baseline plaque volume (mm 3 ) 144.9± ± Baseline percent plaque volume (%) 72.37± ± PEI 6.15± ± PEI >3 27 (93.1%) 15 (53.6%) <0.001 Calcium arc >90 18 (62.1%) 15 (56.5%) Calcium arc Post-interventional IVUS Residual percent plaque area (%) 55.8± ± Values are n (%) or mean SD. DM, diabetes mellitus; IVUS, intravascular ultrasound; PEI, plaque eccentricity index. Theoretically, because sirolimus and everolimus stop proliferation in the G1 S phase of the cell cycle by phosphatidylinositol-3 kinase-mediated inhibition of the mammalian target of rapamycin, the prevention of restenosis by limus derivatives may be hampered by insulin resistance, unlike the case with paclitaxel. Nevertheless, results from clinical studies have been conflicting. Two recent randomized trials showed that significant improvements in TVR and stent thrombosis were limited to the non-diabetic subgroup of patients, 7,19 while Grube et al showed in the SPIRIT V Diabetic Study that implantation of EES rather than paclitaxel-eluting stents enabled better inhibition of intimal hyperplasia with a comparable safety outcome. 20 Furthermore, Sakata et al have shown through serial IVUS analysis that neointima suppression by EES in patients with and without DM is comparable. 21 Given the lack of difference in the average neointimal thickness between EEStreated patients with and without DM observed in that study, the present study results are consistent, and theoretical differences in the mechanism of action may not be translated into the efficacy of EES. Stent Expansion in DM vs. Non-DM Patients Several studies have shown that asymmetric stent expansion may affect the pattern of neointimal growth after deployment of DES. 22,23 In our recent OCT study of lesions treated with sirolimus-eluting stents, we found that a significant inverse relationship existed between the extent of asymmetric stent expansion and inhomogeneous neointimal suppression using the

8 OCT Study of EES in DM Patients 2195 Study Limitations First, this study had a relatively limited sample size, which raises the possibility of selection bias. Also, as is often the case with this type of retrospective observational study, we did not perform power calculation, which can cause a type 2 error. Second, the follow-up period was limited to 17 months, warranting further observation to clarify the effect of these OCT results on more long-term clinical outcomes. Third, pre-interventional OCT data were unavailable for analysis because of the inherent difficulties in performing OCT examination in the case of severe stenotic lesions. Fourth, difference in the baseline patient backgrounds such as the percentage of unstable angina and in-stent restenotic lesions may have affected the results of the present study. However, although we re-conducted the analysis throughout only in de novo lesions, the results were quite similar (Tables S3 S7). Also, considering that such factors were not independently associated with important OCT findings (eg, SEI, NUS, and thrombus) by multivariate analysis, we currently consider that the effect of such differences would be small. Finally, the difference in the absolute values of SEI and NUS was quite small, though significant. Because of limited numbers of patients and the use of nonstandard parameters (SEI and NUS), the clinical relevance of these findings is still unclear. These limitations warrant further studies in adsame methodology as in the present study. 10 In this study, EES implanted in DM patients showed greater asymmetric stent expansion than in those without DM. In addition, there was also a weak, but significant, inverse relationship between the extent of asymmetric stent expansion and inhomogeneous neointimal suppression, which is consistent with the results of the previously mentioned study. 21 In the current study, EES successfully attenuated the overall neointimal proliferation and luminal narrowing, regardless of the presence or absence of DM. Nevertheless, DM has been previously shown to be associated with increased risk of ISR, TLR, or TVR. 1,4,5 Inhomogeneous neointimal suppression coupled with a numerically high incidence of thrombus attachment observed in the present study might partly explain this discrepancy in the results. Although the overall extent of neointimal proliferation seemed similar, the incidence of angiographic restenosis tended to be higher for DM than for non-dm lesions. Uneven neointimal suppression in DM might play a role in the relatively higher incidence of angiographic ISR seen in DM. Another reason might be the unfavorable coronary anatomy associated with diabetic lesions, such as smaller vessel size and diffusely diseased vessel. In the present study, quantitative content analysis showed a smaller post-stent MLD with greater late loss in both the proximal and distal stent edges of the lesions in DM patients. Further, the IVUS subgroup analysis showed greater residual plaque burden after stenting. Interestingly, previous investigators have consistently reported an association between greater residual plaque burden at reference vessel segments and edge stenosis in the cohorts of sirolimuseluting, paclitaxel-eluting, and bare metal stent implantation. 24,25 Coupled with the rapid progression of remote or other atherosclerotic lesions and higher incidence of comorbidities in patients with DM, these factors may explain to some degree the higher incidence of future clinical events, even in the DES era, as described by others. 23 In this study, despite achieving a similar lumen area, lesions in patients with DM showed significantly greater asymmetric stent expansion than non-dm lesions and there was a significant relationship between SEI and NUS in the overall population. There are several possible explanations for the asymmetric stent expansion in lesions of DM patients. Theoretically, a denser tissue matrix of plaque and greater stiffness of the vessel wall in the DM patients would hamper stent expansion during implantation. 26 Furthermore, DM patients more often have smaller reference vessels because of diffuse atherosclerosis and inadequate compensatory remodeling. 24,25,27 Indeed, in the IVUS subgroup of the present study, lesions in DM patients showed greater plaque volume with a higher incidence of asymmetric plaque than those in non-dm patients. These plaque characteristics, coupled with smaller, less compliant reference vessels may be responsible for the less-then-ideal stent expansion seen in DM patients. Despite our OCT findings, none of the EES-treated patients in the current study experienced stent thrombosis up to 1 year after the index procedure. The sample size and follow-up duration were limited, and the study was not powered to clarify this or other clinical outcomes. A recent large-scale pooled study has indicated an attenuation of the safety advantage of EES in DM patients. 28 Among patients treated with EES, the 2-year rates of most adverse events (MI, TLR, and stent thrombosis) were the lowest in non-dm patients, intermediate in DM patients not receiving insulin treatment, and the highest in insulin-treated DM patients. Interestingly, the DM patients with insulin showed the greatest asymmetric stent expansion and uneven neointimal distribution followed by DM patients with- out insulin and non-dm lesions (ANOVA P=0.018 for NUS, ANOVA P=0.002 for SEI; Figures 2B,C). These finding may support the results from previous clinical studies from a mechanistic perspective. Local Vessel Healing and Future Clinical Events In the current study, use of EES successfully attenuated overall neointimal proliferation and luminal narrowing, regardless of the presence or absence of DM. Nevertheless, DM has previously been shown to be associated with increased risk of ISR, TLR, or TVR. 1 3 Previous reports, including ours, have already demonstrated that uneven neointimal distribution is associated with intrastent thrombus after sirolimus-eluting stent as well as paclitaxel-eluting stent implantation. 10,22 Especially in diabetic patients, platelet activation is known to be increased by increased fibrinogen, thrombin, and factor VII activation. 29 Also, DM is an inflammatory proliferative disease, and therefore might be susceptible to rheological effects such as low wall shear stress and high oscillatory shear caused by the turbulent flow induced by uneven neointimal distribution, which would probably lead to prooxidant, proatherosclerotic, and procoagulative status. 7 Inhomogeneous neointimal suppression coupled with the high incidence of thrombus attachment observed in the present study might partly explain this discrepancy in our results. Another reason might be the unfavorable coronary anatomy associated with lesions in diabetic patients, such as smaller vessel size and diffusely diseased vessel. In the present study, quantitative content analysis showed a smaller post-stent MLD with greater late loss in both the proximal and distal stent edges of the lesions in DM patients. Further, the IVUS subgroup analysis showed greater residual plaque burden after stenting. Interestingly, previous investigators have consistently reported an association between greater residual plaque burden at reference vessel segments and edge stenosis in the cohorts of sirolimus-eluting stent, paclitaxel-eluting stent, and bare metal stent implantation. 30,31 Coupled with the rapid progression of remote or other atherosclerotic lesions and the higher incidence of comorbidities in patients with DM, these factors may explain to some degree the higher incidence of future clinical events, even in the drug-eluting stent era, as described in some studies. 24

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An integrated TAXUS IV, V, and VI intravascular ultrasound analysis of the predictors of edge restenosis after bare metal or paclitaxeleluting stents. Am J Cardiol 2009; 103: Supplementary Files Supplementary File 1 Figure S1. Study population. Table S1. IVUS substudy population Table S2. Correlation with OCT and IVUS parameters Table S3. Characteristics in de novo patients Table S4. Lesion and procedure characteristics in de novo patients undergoing everolimus-eluting Stent Implantation with and without DM Table S5. OCT data and analysis in de novo patients undergoing everolimus-eluting stent implantation with and without DM Table S6. Factors correlated to stent eccentricity index in de novo patients with everolimus-eluting stent implantation Table S7. Clinical events (median 484 days) in de novo patients with and without DM Please find supplementary file(s);