Clinical Investigations

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1 Clinical Investigations Serial Angioscopic Evaluation of Neointimal Coverage and Incidence of Thrombus Formation After Paclitaxel-Eluting Stent Implantation: Comparison Between 6- and 18-Month Follow-Up Address for correspondence: Masami Nishino, MD, PhD, FACC Division of Cardiology Osaka Rosai Hospital Nagasone-cho, Kita-ku, Sakai Osaka , Japan Masahiko Hara, MD; Masami Nishino, MD, PhD, FACC; MasayukiTaniike, MD, PhD; Nobuhiko Makino, MD, PhD; Hiroyasu Kato, MD; Yasuyuki Egami, MD; Ryu Shutta, MD; Jun Tanouchi, MD, PhD; Yoshio Yamada, MD, PhD Divisionof Cardiology,Osaka Rosai Hospital, Sakai, Osaka, Japan Background: Long-term serial angioscopic follow-up data after paclitaxel-eluting stent (PES) implantation has not previously been published. The aim of this study is to compare the angioscopic parameters such as neointimal coverage grade and prevalence of red mural thrombus at 6- and 18-month follow-up after PES implantation. Hypothesis: Neointimal formation continues to grow and prevalence of angioscopic thrombus formation becomes low over time after PES implantation. Methods: We retrospectively enrolled 17 patients with 19 stents who underwent both 6- and 18-month follow-up coronary angioscopy after PES implantation. We evaluated the minimum and maximum neointimal coverage grade within 1 stent using coronary angioscopy by classifying neointimal coverage grade into 4 categories. Neointimal coverage grade and incidence of angioscopic red mural thrombus were compared between 6- and 18-month follow-up groups. Results: Minimum neointimal coverage grade at 18 months become lower than that at the 6-month follow-up (0.95 ± 0.62 at 6 mo vs 0.58 ± 0.51 at 18 mo, P = 0.035), whereas maximum grade was not significantly different (2.16 ± 0.83 at 6 mo vs 2.37 ± 0.76 at 18 mo, P = 0.248). High incidence of angioscopic red mural thrombus at 6 months was maintained even at 18-month follow-up (68% at 6 mo vs 84% at 18 mo, P = 0.224). Conclusions: Long-term serial angioscopic follow-up demonstrated persistent high incidence of red mural thrombus formation at 18 months after PES implantation. Introduction Drug-eluting stents (DES) were developed to reduce the restenosis rate compared with bare-metal stent (BMS) by inhibiting in-stent neointimal hyperplasia. 1 3 The paclitaxeleluting stent (PES) is a first-generation DES, and serial angiographic and intravascular ultrasound (IVUS) study has demonstrated that neointimal suppression is sustained at 2 years after PES implantation. 4 However, long-term serial angioscopic follow-up data after PES implantation has not previously been published. The aim of this study was to evaluate and compare the angioscopic parameters such as neointimal coverage grade and prevalence of red mural thrombus formation at 6- and 18-month follow-up after PES implantation. The authors have no funding, financial relationships, or conflicts of interest to disclose. 322 DOI: /clc Wiley Periodicals, Inc. Methods Study Patients We retrospectively enrolled 17 patients with 19 stents who underwent both 6- and 18-month follow-up coronary angioscopy after PES implantation (Taxus Express 2 ;Boston Scientific, Natick, MA). All stents were implanted for the treatment of de novo lesions between June 2007 and December 2007 at Osaka Rosai Hospital. Sixteen patients (18 stents) underwent PES implantation for stable angina pectoris and 1 patient (1 stent) underwent PES implantation for acute coronary syndrome, as shown in Table 1. Thus, the present study was performed using previously reported data on 17 of 35 patients at 6-month follow-up 5 and previously reported data on 16 of 20 patients at 18-month follow-up after PES implantation by adding 1 other patient at 18-month follow-up. 6 Only patients who underwent both 6- and 18-month follow-up angioscopy after PES implantation were recruited in this subsample study. Thus, all 17 patients and 19 stents were the same candidates, Received: September 6, 2010 Accepted with revision: November 24, 2010

2 Table 1. Baseline Characteristics Patient Characteristics (n = 17) Age, y 70 ± 8 Male sex 15 (88) ACS 1 (6) Major coronary risk factors Hypertension 14 (82) DM 7 (41) Smoking 12 (71) Dyslipidemia 14 (82) Lesion Characteristics (n = 19) ACS 1 (5) Target lesion LAD 6 (32) LCx 1 (5) RCA 12 (63) Lesion type B1 1 (5) B2 3 (16) C 15(79) Stent diameter (mm) 3.17 ± 0.26 Stent length (mm) 25.5 ± 6.3 Abbreviations: ACS, acute coronary syndrome; DM, diabetes mellitus; LAD, left anterior descending artery; LCx, left circumflex artery; RCA, right coronary artery. Data are presented as mean ± SD or n (%). and were examined at both time points. Patients with major adverse cardiac events during the follow-up period were excluded from the study. We evaluated and compared patient characteristics, lesion characteristics, and coronary angioscopic parameters at 6- and 18-month follow-up. The Osaka Rosai Hospital ethics committee approved this study, and we obtained written informed consent from all patients before catheterization. No extramural funding was used to support this study. The study was in accordance with the Declaration of Helsinki. Antiplatelet Regimen All patients took 100 mg aspirin daily during the follow-up period. Ticlopidine (200 mg) was given additionally as a dual antiplatelet regimen for at least 6 months after PES implantation because clopidogrel became available in Japan in October Ticlipidine was replaced by clopidogrel (75 mg) from October 2007 or ceased at the attending physician s discretion after the 6-month follow-up evaluation. Angioscopic Technique and Analysis Detailed methodology has previously been reported elsewhere. 5,6 After administration of 5000 U of intravenous heparin and coronary angiography, we performed 6000 pixel resolution angioscopy (Fiber catheter; Fiber Tech, Chiba, Japan) with a transradial approach using a 6.0F guide catheter. The optical fiber, which was contained in a 4.0F inner catheter, was manually pulled back from the distal edge of the stent to the proximal edge under careful angioscopic and angiographic guidance. Angioscopic images were obtained during dextran solution injection and were recorded on digital video discs for subsequent offline analysis. We classified neointimal coverage into 4 grades 5,6 :grade 0, stent struts showing glistening metallic luster without neointima, as seen immediately after stent implantation; grade 1, stent struts with very thin neointimal coverage, with metallic color but without metallic luster; grade 2, stent struts without metallic color but not fully embedded in neointima; and grade 3, full neointimal coverage with no struts visible (Figure 1). We first evaluated the entire stented segment using angioscopy under fluoroscopic guidance, and then chose one strut that had the lowest grade as the minimum grade and one with the highest grade as the maximum grade. We also evaluated the presence of red mural thrombus formation, defined as a coalescent red superficial or protruding mass that could not be flushed out by dextran solution injection (Figure 1). We only evaluated whether there was a thrombus or not. The prevalence of thrombus was determined dichotomously and analyzed as nominal variable. We assessed and compared these angioscopic Figure 1. Representative images of neointimal coverage grade. Neointimal coverage was classified into 4 grades: grade 0, stent struts showing glistening metallic luster without neointima, as seen immediately after stent implantation; grade 1, stent struts with very thin neointimal coverage with metallic color but without metallic luster; grade 2, stent struts without metallic color but not fully embedded in neointima; grade 3, full neointimal coverage with no struts visible. Arrows indicate stent struts with focusing neointimal coverage grade. Red mural thrombi are seen at the left side of the panel ( ). 323 DOI: /clc Wiley Periodicals, Inc.

3 parameters at 6- and 18-month follow-up. It is difficult to analyze exactly the same part of the stent or same thrombus in serial follow-up study using this coronary angioscopy system, because there were no measures in the coronary arteries during angioscopic evaluation. Two independent observers blinded to patient and stent information analyzed the angioscopic images to determine the inter-rater reliability of the angioscopic analysis. Statistical Analysis All statistical analyses were performed using SPSS for Windows, version 11.0 (SPSS Inc., Chicago, IL). Discrete variables are reported as number (percentages) and compared by χ 2 statistics. Continuous and ordinal variables were reported as mean ± SD. We employed paired t test for analyzing continuous variables and Wilcoxon signed-rank test for analyzing ordinal variables. A value of P < 0.05 was considered statistically significant. Inter-rater reliability of neointimal coverage grades was evaluated by Cohen s kappa coefficient. A value of Cohen s kappa coefficient >0.80 was considered to be almost perfect agreement. Results Patient and Lesion Characteristics Table 1 shows baseline patient and lesion characteristics. Table 2 shows serum markers, dual antiplatelet treatment, and late lumen loss at 6- and 18-month follow-up. Lowdensity lipoprotein cholesterol and rate of dual antiplatelet therapyweresignificantlylower at 18-month follow-up than at 6-month follow-up. Angioscopic Findings Figure 2 shows the temporal changes of neointimal coverage grades. Minimum neointimal coverage grade Table 2. Serum Markers, Antiplatelet Therapy, and Late Lumen Loss at 6- and 18-Month Follow-Up 6 Months 18 Months P Value Follow-up period, d 191 ± ± 22 Serum markers HbA 1c (%) 6.0 ± ± LDL cholesterol (mg/dl) 95 ± ± HDL cholesterol (mg/dl) 45 ± ± High-sensitivity CRP (mg/dl) Estimated GFR (ml/min/1.73 m 2 ) Dual antiplatelet therapy at follow-up 0.12 ± ± ± ± (100) 7 (37) <0.001 Late lumen loss (mm) 0.33 ± ± Abbreviations: CRP, C-reactive protein; GFR, glomerular filtration rate; HbA 1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, lowdensity lipoprotein. Data are presented as mean ± SD or n (%). become lower at 18-month follow-up than at 6 months, whereas there was no statistically significant difference in maximum grade between the 2 time points. The incidence of red mural thrombus did not alter significantly between the 2 time points (68% at 6 mo vs 84% at 18 mo, P = 0.224). Cohen s kappa coefficients for the evaluation of inter-rater reliability were 0.943, 0.830, and 0.930, for minimum grade, maximum grade, and presence of red mural thrombus, respectively. These data suggested almost perfect agreement between the 2 observers. Figure 3 shows angioscopic images from a patient who showed regressive neointimal coverage grade without thrombi. Discussion We found that minimum neointimal coverage grade become significantly lower at 18-month follow-up than at 6-month follow-up, whereas maximum neointimal coverage grade did not change significantly between the 2 time points, although the amount of endothelial cover on the stent struts is subjective and less convincing with few numbers. Several kinds of temporal changes in neointimal formation have previously been reported both in BMS and sirolimus-eluting stents (SES). For example, coronary angioscopy showed that there was initial thickening of the neointima that became nontransparent at 6 months in BMS. Thereafter, the neointima became thin and transparent. 7 This neointimal regression after BMS implantation is correlated with an increase in the luminal diameter measured by quantitative coronary angiography (QCA), 4,8 and a decrease in neointimal area inside the stent measured by IVUS. 4 In contrast, serial angioscopic evaluation of 17 patients for 2 years after SES implantation showed that neointimal coverage increased significantly over time. 9 This result is consistent with long-term angiographic and IVUS follow-up data after SES implantation. 10 A serial angiographic and IVUS study of PES, however, found discrepancy between the change in neointimal area and the change in minimum lumen diameter. 4 Aoki et al reported that late lumen loss, assessed by QCA, decreased between 6 months to 2 years after PES implantation, whereas neointimal area, assessed by IVUS, increased over the same period. 4 We found that minimum neointimal coverage grade became significantly lower at the 18-month follow-up than at 6-month follow-up, and there were no statistically significant differences in maximum grade and late lumen loss between the 2 time points. These results suggest that temporal changes in neointimal formation after PES implantation may be different from and more complex than the changes after SES or BMS implantation. However, it appears that the major change driving the regression of minimum grade was an increase in grade 0 and a decrease in grade 1 coverage from 6-month to 18-month follow-up in this study (Figure 2). There is a possibility that uncovered stent struts become visible due to repetitive formation and resorption of thrombi during the 12-month interval. That is, high incidence of red mural thrombus formation might obscure many stent struts and might make precise evaluation of neointimal coverage difficult. Thus, it is also possible that high incidence of red mural thrombus formation might lead to discrepancies 324

4 Figure2. Temporal changes of neointimal coverage grades. Dataare presented as mean ± SD, and analyzed with the Wilcoxon signed-rank test. among angiographical, angioscopic, and IVUS analyses of neointimal coverage after PES implantation. We believe our findings provide incremental data and insights into neointimal development after PES implantation. Because the mechanism of neointimal regression may result from the decrease in cellular components partly due to apoptosis and neointimal sclerosis, 11,12 we speculated that excessive apoptosis is one of the possible mechanisms if this regressive neointimal formation was truly present (Figure 3). We also found the incidence of angioscopic red mural thrombus to be similar at 6- and 18-month follow-up. Several angioscopic studies showed PES had a higher incidence of mural thrombus than SES at 6 months after stent implantation. 5,13 As the mural thrombus is believed to be one of the arterial healing processes, 14 the high incidence of mural thrombus we found at 18 months might thus be a consequence of a sustained or slow healing process after PES implantation. A relatively lower rate of dual antiplatelet therapy at 18-month follow-up compared with 6-month follow-up may account for the high incidence of angioscopic thrombus formation at 18-month follow-up. It is also possible that regression of minimum neointimal coverage is correlated with higher incidence of thrombus formation at 18-month follow-up because there is a correlation between uncovered stent struts and thrombus formation. 5,15 There is a concern that the risk of very late stent thrombosis is higher with DES than BMS. 16 Although many of angioscopic red mural thrombi are believed to be subclinical, 5,6 very high incidence of thrombus formation at 18 months after PES implantation will support the recommendation to extend dual antiplatelet therapy for longer than 12 months. 17,18 Study Limitations This study had several limitations. First, this was a singlecenter, nonrandomized retrospective observational study with a small sample size and no control groups. Second, angioscopy is limited in the evaluation of the quantification of neointimal coverage, even though this study demonstrated an adequate inter-rater reliability for the angioscopic Figure 3. Angioscopic images froma patient who showed regressive neointimal coverage grade without thrombi. A 65-year-old male with a mm PES implanted in the distal portion of the RCA. (A) At 6-month follow-up, coronary angioscopy showed grade 3 neointimal coverage of the whole stent (B D). At 18-month follow-up, coronary angioscopy showed grade 2 neointimal coverage at the proximal portion (E), grade 1 at the middle (F), and grade 2 at the distal portion of the stent (G). The minimum grade had regressed from 3 to 1 and the maximum grade from 3 to 2. Abbreviations:LAO, left anterior oblique; PES, paclitaxel-eluting stent; RCA right coronary artery. 325

5 evaluations. Third, it is unclear whether the evaluation of neointimal coverage at maximal and minimal coverage site represents the entire stent coverage, although neointimal coverage occurs consecutively. Fourth, high incidence of red mural thrombus formation might obscure many stent struts, and might make precise evaluation of neointimal coverage difficult. Finally, the virtual impossibility of analyzing exactly the same part of the stent or same thrombus is a major limitation in serial follow-up study using coronary angioscopy. Conclusion Long-term serial angioscopic follow-up demonstrated the persistent high incidence of red mural thrombus formation at 18 months after PES implantation. Further large-scale clinical studies are needed to confirm our results and clarify the clinical impact. References 1. Stettler C, Wandel S, Allemann S, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network metaanalysis. Lancet. 2007;370: Marroquin OC, Selzer F, Mulukutla SR, et al. A comparison of bare-metal and drug-eluting stents for off-label indications. NEngl JMed.2008;358: Costa MA, Simon DI. Molecular basis of restenosis and drugeluting stents. Circulation. 2005;111: Aoki J, Colombo A, Dudek D, et al; TAXUS II Study Group. Persistent remodeling and neointimal suppression 2 years after polymer-based, paclitaxel-eluting stent implantation: insights from serial intravascular ultrasound analysis in the TAXUS II study. Circulation. 2005;112: Hara M, Nishino M, Taniike M, et al. Difference of neointimal formational pattern and incidence of thrombus formation among 3 kinds of stents: an angioscopic study. JACC Cardiovasc Interv. 2010;3: Hara M, Nishino M, Taniike M, et al. High incidence of thrombus formation at 18 months after paclitaxel-eluting stent implantation: angioscopic comparison with sirolimus-eluting stent. Am Heart J. 2010;159: Asakura M, Ueda Y, Nanto S, et al. Remodeling of in-stent neointima, which became thinner and transparent over 3 years: serial angiographic and angioscopic follow-up. Circulation. 1998;97: Kimura T, Yokoi H, Nakagawa Y, et al. Three-year follow-up after implantation of metallic coronary-artery stents. N Engl J Med. 1996;334: Awata M, Kotani J, Uematsu M, et al. Serial angioscopic evidence of incomplete neointimal coverage after sirolimus-eluting stent implantation: comparison with bare-metal stents. Circulation. 2007;116: Degertekin M, Serruys PW, Foley DP, et al. Persistent inhibition of neointimal hyperplasia after sirolimus-eluting stent implantation: long-term (up to 2 years) clinical, angiographic, and intravascular ultrasound follow-up. Circulation. 2002;106: Schatz RA, Palmaz JC, Tio FO, et al. Balloon-expandable intracoronary stents in the adult dog. Circulation. 1987;76: Isner JM, Kearney M, Bortman S, et al. Apoptosis in human atherosclerosis and restenosis. Circulation. 1995;91: Takano M, Yamamoto M, Murakami D, et al. Lack of association between large angiographic late loss and low risk of instent thrombus: angioscopic comparison between paclitaxel-and sirolimus-eluting stents. Circ Cardiovasc Interv. 2008;1: Komatsu R, Ueda M, Naruko T, et al. Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses. Circulation. 1998;98: Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation. 2007;115: Lüscher TF, Steffel J, Eberli FR, et al. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation. 2007;115: Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297: Van Werkum JW, Heestermans AA, Zomer AC, et al. Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry. J Am Coll Cardiol. 2009;53: