Potential Benefit of Final Kissing Balloon Inflation After Single Stenting for the Treatment of Bifurcation Lesions

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1 Circulation Journal Official Journal of the Japanese Circulation Society ORIGINAL ARTICLE Cardiovascular Intervention Potential Benefit of Final Kissing Balloon Inflation After Single Stenting for the Treatment of Bifurcation Lesions Insights From Optical Coherence Tomography Observations Hirotoshi Hariki, MD; Toshiro Shinke, MD; Hiromasa Otake, MD; Junya Shite, MD; Masayuki Nakagawa, MD; Takumi Inoue, MD; Tsuyoshi Osue, MD; Masamichi Iwasaki, MD; Yu Taniguchi, MD; Ryo Nishio, MD; Noritoshi Hiranuma, MD; Hiroto Kinutani, MD; Akihide Konishi, MD; Ken-ichi Hirata, MD Background: Treatment of coronary bifurcation lesions using a single stenting strategy is preferable over that using a 2-stent technique. The benefit of final kissing inflation (FKI), however, has not been established. Methods and Results: Seventy-two patients (76 lesions) with true bifurcation lesions treated with a single drugeluting stent with FKI (n=33 lesions) or without FKI (non-fki, n=43 lesions) were enrolled in this study. Optical coherence tomography (OCT) was performed at 6 12 months after implantation. Based on the OCT findings, the percentage of jailing struts (number of jailing struts/total number of struts at the bifurcation lesion) was calculated. Percentage of uncovered struts and frequency of thrombus attachment were each evaluated at the proximal, bifurcation, and distal segments. Major adverse cardiac events (MACE) were also evaluated. The percentage of jailing struts was significantly lower in the FKI than in the non-fki group (5.8±6.2% vs. 17.3±6.1%, P<0.01). Thrombus attachment was less frequent in the FKI group (24.2% vs. 46.5%, P=0.046), especially at side-branch orifices (3.0% vs. 27.9%, P<0.001). The percentage of uncovered struts was lower in the FKI than non-fki group at the proximal, bifurcation, and distal segments. The incidence of MACE was not different in this small cohort. Conclusions: FKI might reduce the frequency of subclinical thrombus possibly by reducing the number of jailing struts. (Circ J 2013; 77: ) Key Words: Coronary artery disease; Drug-eluting stent; Optical coherence tomography; Thrombus benefit of routine FKI after single stenting of bifurcation lesions. 6 In addition, inadequate side-branch dilatation may result in stent deformation or incomplete stent apposition. 7 In contrast, quantitative coronary angiography (QCA) conducted in the Nordic-Baltic Bifurcation Study III showed better expansion of the side-branch orifice in the FKI group. 6 Because delayed arterial healing characterized by exposed stent struts is considered a possible risk factor for stent thrombosis, 8 struts floating at the side-branch orifice (jailing strut) could affect thrombus formation after DES implantation. Despite these controversies, the relationship between stenting strategies and local findings, such as stent apposition, thrombus formation, and neointimal coverage, which may be associated with long-term clinical outcome, has not been well evaluated to date. Several studies have shown that the high resolution of optical coherence tomography (OCT) enables visualization of coronary arteries at the micron level for evaluation of strut cover- Percutaneous coronary intervention (PCI) using drugeluting stents (DES) reduces restenosis and major adverse cardiac events (MACE) compared to PCI with bare metal stents. 1 Even in the DES era, however, the procedures for bifurcation remain complex and challenging. 2,3 The single-stent strategy is currently considered preferable because the 2-stent strategy has higher rates of periprocedural myocardial infarction and long-term MACE, 4,5 which is probably associated with the increased use of contrast and prolonged procedure time. Therefore, a 1-stent strategy with a provisional approach to the side branch with final kissing inflation (FKI) might be the most acceptable strategy in clinical practice. Recently, the Nordic-Baltic Bifurcation Study III, a randomized comparison of clinical outcomes in patients with coronary bifurcation lesions treated with FKI vs. without FKI after main vessel (MV) stenting, found a similar 6-month clinical outcome between the 2 groups, raising questions regarding the Received July 2, 2012; revised manuscript received January 12, 2013; accepted January 20, 2013; released online February 27, 2013 Time for primary review: 38 days Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan Mailing address: Toshiro Shinke, MD, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kusunoki-cho, Chuo-ku, Kobe , Japan. shinke@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 1194 HARIKI H et al. Figure 1. Segment location in the bifurcation lesion: bifurcation segment was analyzed for every cross-section and proximal, distal segments were analyzed every 1 mm. age and thrombus formation Thus, the purpose of the retrospective study was to assess the local tissue changes and thrombus formation at 6 12 months after DES implantation using OCT, and its impact on long-term clinical events. Methods Subjects Between October 2004 and February 2010, 173 patients underwent elective PCI with a sirolimus-eluting stent (SES; Cypher, Cordis, Miami Lakes, FL, USA) or a paclitaxel-eluting stent (PES; Taxus Liberte, Boston Scientific, Natick, MA, USA) for de novo native coronary true bifurcation lesions. A true bifurcation lesion was defined as (1,1,1), (1,0,1), or (0,1,1,) by the Medina classification. 11 Among these patients, a total of 110 patients were retrospectively enrolled in this study, according to the inclusion criteria MV diameter 2.5 mm and side-branch diameter 2.0 mm on visual estimate. FKI was not randomly performed, but performed at operator discretion using a pressure of 6 8 atm after stent implantation using balloons suitable for the MV and side-branch diameter. Procedure time and contrast volume used during PCI were compared between lesions treated with and without FKI. Peak creatine kinase (CK)-MB level after PCI procedure within 24 h was also evaluated and compared between the groups. All patients successfully underwent PCI and 84 patients consented to repeat QCA and OCT at 6 12 months after PCI. Inadequate OCT images were excluded, and 39 patients (43 lesions; SES, n=27; PES, n=16) treated without FKI and 33 patients (33 lesions; SES: n=22, PES: n=11) treated with FKI were evaluated. In the present study, PCI was performed with intravascular ultrasound (IVUS) guidance and we verified the optimal stent expansion and strut apposition using the IVUS images obtained at the end of the index PCI procedure. All patients were taking aspirin (100 mg/day), and either ticlopidine (200 mg/day) or clopidogrel (75 mg/day) was also given for at least 6 months after DES implantation, because clopidogrel was not approved for clinical use until May 2006 in Japan. This study was approved by the ethics committee of Kobe University and all enrolled study patients provided written informed consent to participate in the study. QCA QCA of the bifurcation lesion was obtained in 3 segments: the MV proximal segment, the MV distal segment, and the side branch. We measured the minimum lumen diameter (MLD) and the reference diameter and percent diameter stenosis at each lesion. QCA parameters were evaluated for the target lesion before and after PCI and at the time of QCA follow-up using dedicated software (QCA-CMS 5.1; Medis, Leiden, Netherlands). In-stent late luminal loss was defined as the difference between MLD immediately after the procedure and that at follow-up. Binary restenosis was defined as >50% residual stenosis. To assess the relationship between vessel reference diameter and balloon diameter, we correlated balloon:artery ratios as balloon diameter divided by vessel reference diameter measured on QCA. We measured balloon:artery ratios separately at proximal MV, distal MV and side branch. The proximal MV balloon size for FKI was measured as theoretical mean hugging balloon diameter, as defined in a previous study. 12

3 Potential Benefit of Final Kissing Inflation 1195 OCT In this study, we used the M2 OCT system. OCT was performed as previously reported. 10 Briefly, a in OCT catheter (ImageWire; LightLab Imaging, Westford, MA, USA) was advanced to the distal end of the MV-stented lesion through an occlusion balloon catheter (HeliosTM; LightLab Imaging). To clear the blood from the field of view, the occlusion balloon was inflated to 0.5 atm at the proximal site of 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 with an automatic pullback device moving at 1 mm/s. OCT Analysis All images were analyzed by an independent observer who was blinded to the clinical presentation and lesion characteristics. We divided in-stent lesions into 3 segments: proximal, bifurcation, and distal segments (Figure 1). For cross-section analysis of the bifurcation lesions, we defined the distal crosssection as the last cross-section in which the contour was not distorted by the side branch, guided by the longitudinal OCT reconstruction. The proximal cross-section was defined as the first cross-section in which the contour was not distorted by the side branch. The bifurcation segment was defined as the segment between the proximal cross-section and the distal cross-section. The distal segment and proximal segment were defined as the segments distal from the distal cross-section and proximal from the proximal cross-section, respectively. Lumen Stent Area Measurement Lumen area and stent area, maximum stent diameter, and minimum stent diameter Figure 2. Optical coherence tomography analysis at the bifurcation segment: AO, vessel wall adjacent to the ostium; OO, half the circumference of the vessel wall opposite the ostium; SO, side-branch ostium. at the proximal and distal cross-sections were measured. Percent neointimal hyperplasia (%NIH) was calculated as ([stent area lumen area]/stent area). To evaluate the asymmetric expansion of the stent, we calculated the stent eccentricity index as the minimum stent diameter/maximum stent diameter. 8 Strut-Based Analysis In the distal and proximal segments, Figure 3. Classification of jailing struts at the side-branch ostium: uncovered (no tissue visible on the jailing strut); covered (tissue proliferation on the adluminal surface of the strut); and proliferative (strut fully encapsulated by tissue or tissue connecting adjacent struts). Definition of intracoronary thrombus: protruding mass with signal attenuation on optical coherence tomography.

4 1196 HARIKI H et al. Table 1. Patient and Lesion Characteristics Non-FKI FKI P-value Patients n Age (years) 71.6± ± Male 29 (74.4) 24 (72.7) 0.88 Hypertension 35 (89.7) 32 (97.0) 0.54 Diabetes 20 (51.3) 16 (48.5) 0.81 Smoking 25 (64.1) 20 (60.6) 0.76 Hyperlipidemia 29 (74.4) 27 (81.8) 0.45 CKD 12 (30.8) 8 (24.2) 0.54 Hemodialysis 4 (10.3) 2 (6.1) 0.68 Clinical diagnosis 0.54 Stable angina pectoris 27 (69.2) 25 (75.8) Unstable angina pectoris 12 (30.8) 8 (24.2) Lesions n Vessel treated LMT/LAD/LCX/RCA 1/18/12/12 5/17/9/ Procedure characteristics Stent diameter (mm) 2.87± ± Stent length (mm) 23.6± ± Maximum balloon diameter Proximal main vessel 2.93± ±0.36* <0.01 Distal main vessel 2.93± ± Side branch NA 2.33±0.30 Balloon:artery ratio Proximal main vessel 1.05± ±0.18 <0.01 Distal main vessel 1.12± ± Side branch NA 1.05±0.17 Max. inflation pressure (atm) 15.9± ± Procedure time (min) 95.9± ± Contrast (ml) 193±67 201± Peak CK-MB (mg/dl) 26.2± ± Medina classification 1,1,1/1,0,1/0,1,1 32/4/7 27/2/ Follow-up (months) 7.24± ± Data given as mean ± SD or n (%). *Estimated by theoretical mean hugging balloon diameter. CK-MB, creatine kinase-mb; CKD, chronic kidney disease; FKI, final kissing inflation; LAD, left anterior descending artery; LCX, left circumflex artery; LMT, left main trunk; RCA, right coronary artery. OCT images were analyzed for 5 cross-sections adjacent to the bifurcation segment at 1-mm intervals (every 15 frames). For cross-section analysis, we evaluated stent strut apposition and measured neointimal thickness. An uncovered strut was defined as that with a neointimal thickness of 0 μm. The frequency of uncovered struts was calculated as the number of those struts divided by the number of total struts for each stent. Malapposition was defined as a maximum distance >170 μm in SES and >130 μm in PES between the center reflection of the strut and the adjacent vessel surface. 10 The prevalence of strut malapposition was evaluated for each segment. In the bifurcation segment, we analyzed every cross-section (all frames). To evaluate the axial tissue distribution and to distinguish a stent strut at the side-branch orifice (jailing strut) from a malapposed strut, cross-section OCT images were divided into 3 sites: side-branch ostium (SO); half the circumference of the vessel wall opposite the ostium (OO); and the vessel wall adjacent to the ostium (AO; Figure 2). 9 We defined %jailing strut as the number of SO struts divided by the total number of struts in the bifurcation segment. Based on attached tissue surrounding the jailing strut at the SO region, we classified jailing struts into 3 categories: uncovered; covered (covered only on the MV luminal surface); and proliferative (strut fully encapsulated by tissue or tissue connecting adjacent struts). 9 Intracoronary thrombus was defined as a protruding mass beyond the stent strut into the lumen with significant attenuation behind the mass (Figure 3). 8 Thrombus was identified and counted only when mass protrusion occupied a certain space clearly beyond the strut blooming, and signal attenuation by the thrombus was able to be differentiated from the shadow of the strut. Long-Term Clinical Follow-up Long-term (beyond 8 months, until December 2010) clinical follow-up data were obtained from outpatient record reviews or telephone interviews (non-fki group: range,

5 Potential Benefit of Final Kissing Inflation 1197 Table 2. QCA Results Proximal main vessel Distal main vessel Side branch Non-FKI FKI P-value Non-FKI FKI P-value Non-FKI FKI P-value Before PCI RD (mm) 2.86± ± ± ± ± ± MLD (mm) 1.47± ± ± ± ± ± %DS 54±22 53± ±18 58± ±14 58± After PCI MLD (mm) 2.56± ±0.37 < ± ± ± ±0.38 <0.01 %DS 9±8 6± ±8 10± ±18 32±15 <0.01 Follow-up MLD (mm) 2.45± ± ± ± ± ±0.46 <0.01 %DS 18±17 13± ±13 18± ±19 36±18 <0.01 >50% residual DS 1/43 (2.3) 1/33 (3.0) /43 (2.3) 1/33 (3.0) /43 (58.1) 8/33 (24.2) <0.01 In-stent late luminal loss (mm) 0.11± ± ± ± ± ± Data given as mean ± SD or n (%). %DS, %diameter stenosis; FKI, final kissing inflation; MLD, minimum lumen diameter; PCI, percutaneous coronary intervention; QCA, quantitative coronary angiography; RD, reference diameter. months; median, 25.6±18.7 months; FKI group: range, months; median, 26.2±19.6 months after the index procedure). MACE was defined as cardiac death, myocardial infarction, acute coronary syndrome, and stent thrombosis. Also, target lesion revascularization (TLR) was defined as any reintervention (surgical or percutaneous) to treat luminal stenosis occurring in the same coronary lesion treated at the index procedure. Statistical Analysis Statistical analysis was conducted with StatView version 5.0 (SAS Institute, Cary, NC, USA). Continuous variables are presented as mean ± SD. Differences in continuous parameters between the 2 groups were calculated using unpaired t-test. Categorical variables are presented as frequency counts. Intergroup comparisons were analyzed with Fisher s exact test. Results are reported with the probability value. P 0.05 was considered statistically significant. Results Follow-up QCA and OCT were performed a minimum of 6.0 months after the index PCI (FKI group: range, months; median, 7.9±2.4 months; non-fki group: range, months; median, 7.2±2.4 months). All patients were then clinically monitored by a hospital visit or telephone interview (non-fki group: range, months; median, 25.6±18.7 months; FKI group: range, months; median, 26.2± 19.6 months after the index procedure). The patient characteristics in terms of age, sex, coronary risk factors, or clinical diagnosis were not significantly different between the non- FKI and the FKI groups. Lesion and procedural characteristics were also not different, other than that left main trunk stenting was more frequent in the FKI group (Table 1). The mean interval of follow-up OCT was not different between groups. Maximum inflation pressure at PCI for the MV was similar between the 2 groups. In the FKI group, mean KB dilatation pressure was 7.8±1.4 atm. Mean balloon diameter was 2.9± 0.3 mm for the MV and 2.4±0.3 mm for the side branch. Otherwise, there was no significant difference between the FKI and non-fki groups, including for procedure time, amount of contrast used during PCI, or peak CK-MB level after PCI. Table 3. Morphometry of the Lumen and Stent Area Non-FKI (n=43) FKI (n=33) P-value Lumen area (mm 2 ) Distal 5.98± ± Proximal 6.48± ±2.50 <0.05 Stent area (mm 2 ) Distal 6.92± ± Proximal 7.29± ± %NIH Distal 14.4± ± Proximal 11.7± ± SEI Distal 0.88± ± Proximal 0.86± ± Data given as mean ± SD. FKI, final kissing inflation; %NIH, percent neointimal hyperplasia; SEI, stent eccentricity index (minimum stent diameter/maximum stent diameter). QCA The QCA results are listed in Table 2. The baseline reference vessel diameters were similar between the 2 groups in all segments of the MV and side branch. The FKI group had a significantly greater MLD at the MV proximal segment after PCI with a tendency toward a smaller percent diameter stenosis than the non-fki group. As for the side branch, the MLD was larger and percent diameter stenosis was significantly smaller in the FKI group than in the non-fki group after PCI, and both remained statistically significant at follow-up. In-stent late luminal loss was similar between groups. Balloon:artery ratio at proximal MV was significantly higher in the FKI group. In contrast, the results for the distal MV and side branch were not different between the 2 groups. This shows that the balloons used for FKI were relatively large because of the influence of the dilatation of the 2 balloons. OCT Findings A total of 18,992 struts were identified in 2,446 cross-sectional images on follow-up OCT. Follow-up OCT showed that

6 1198 HARIKI H et al. Figure 4. (A) Percent jailing strut at the bifurcation segment vs. final kissing inflation (FKI). (B) Representative case of jailing strut at the bifurcation segment according to presence of FKI. PES, paclitaxel-eluting stent; SES, sirolimus-eluting stent. Table 4. Percent Uncovered Struts and Frequency of Thrombus Non-FKI (n=43) Percent uncovered struts FKI (n=33) P-value Distal segment 11.1± ± Bifurcation segment AO 10.8± ± SO 20.1± ± OO 11.6± ± Proximal segment 12.7± ± Frequency of thrombus Distal segment 3 (7.0) 3 (9.1) 0.74 Bifurcation segment AO 4 (9.3) 0 (0) 0.07 SO 12 (27.9) 1 (3.0) <0.01 OO 3 (7.0) 2 (6.1) 0.87 Proximal segment 5 (11.6) 4 (12.1) 0.95 Data given as mean ± SD or n (%). AO, vessel wall adjacent to the ostium; FKI, final kissing inflation; OO, half the circumference of the vessel wall opposite the ostium; SO, side-branch ostium. (Table 3). At the bifurcation segment, the percentage of jailing struts was significantly lower in the FKI group than in the non-fki group (5.8±6.2% vs. 17.3±6.1%, P<0.01; Figure 4). A malapposed strut was observed in 10 stents (30.3%) in the FKI group and in 20 stents (46.5%) in the non-fki group (P=0.15). The incidence of malapposed struts in the bifurcation segment was not different at the AO (FKI group, 9.1%, 3/33 vs. non- FKI group, 16.3%, 7/43; P=0.36) and OO (FKI group, 9.1%, 3/33 vs. non-fki group, 18.6%, 8/43; P=0.24) segments. In the non-bifurcation segment, however, a significant difference was observed between groups for the frequency of malapposed struts in the proximal segment, but not in the distal segment (proximal segment: FKI group, 9.1%, 3/33 vs. non- FKI group, 27.9%, 12/43; P=0.04; distal segment: FKI group, 12.1%, 4/33 vs. non-fki group, 18.6%, 8/43; P=0.44). This suggests that FKI resulted in good expansion in the proximal segment. The incidence of uncovered struts was significantly lower in the FKI group than in the non-fki group in each segment, with the exception of the SO segment (Table 4). Among the jailing struts, the percentages of uncovered, covered, and proliferative struts were similar between the 2 groups (uncovered, 20.1% vs. 18.7%, P=0.87; covered, 6.1% vs. 9.6%, P=0.31; proliferative, 73.8% vs. 71.7%, P=0.83). Mean neointimal thickness did not differ significantly between the groups in the distal segment (FKI group, 137.6±97.0 μm; non-fki group, 105.5± 73.6 μm; P=0.105), AO segment (FKI group, 117.2±79.5 μm; non-fki group, 103.4±74.8 μm; P=0.44), OO segment (FKI group, 142.3±105.3 μm; non-fki group, 113.5±104.3 μm; P=0.24), or proximal segment (FKI group, 103.6±78.6 μm, nonmean lumen and stent area of the proximal segment were significantly greater in the FKI group. The stent eccentricity index in the proximal segment was smaller in the FKI group than in the non-fki group, probably due to the FKI procedure. %NIH was similar in all segments between the 2 groups

7 Potential Benefit of Final Kissing Inflation 1199 FKI group, 94.7±63.2 μm; P=0.59). Thrombus attachment was less frequently observed in the FKI group (24.2%, 8/33 stents) than in the non-fki group (46.5%, 20/43 stents; P=0.046). Several stents had plural thrombus attachments spreading over another segment. Especially in the SO region, the frequency of thrombus attached to a jailing strut was significantly lower in the FKI group (3.0%, 1/33 stents) than in the non-fki group (27.9%, 12/43 stents, P<0.01; Table 4). Long-Term Clinical Follow-up At the time of follow-up QCA, no MACE had occurred in the non-fki group and only 1 patient had unstable angina in the FKI group. Three patients in the FKI group and 2 patients in the non-fki group underwent TLR at the time of follow-up QCA and OCT. Long-term clinical follow-up data were obtained for all patients involved in the study. Within the median (ie, long-term) follow-up period (26.2±19.6 months in the FKI group and 25.6±18.7 months in the non-fki group), there were no significant differences in MACE (non-fki, 2.6%; FKI, 6.1%; P=0.41) or TLR (FKI, 9.1%; non-fki, 12.8%; P=0.72) between the 2 groups. Discussion The important findings of the present study are as follows. First, the prevalence of jailing struts at the side-branch orifice, uncovered struts at the bifurcation segment, and malapposed struts at the proximal segment was significantly lower in lesions treated with FKI than in those treated without FKI. Second, overall, OCT detected thrombus in 28 of 76 bifurcation lesions (36.8%). The incidence of thrombus attachment at the side-branch orifice was significantly lower in the FKI group than in the non-fki group. And third, the incidence of MACE did not significantly differ between patients treated with and without FKI after DES implantation. Because this study was an observational retrospective study without randomization for FKI or non-fki, the true impact of FKI on optimal stent apposition and strut coverage remains unclear. The patient characteristics in terms of age, sex, coronary risk factors, or clinical diagnosis, however, were not significantly different between the 2 groups. Also, lesion and procedural characteristics were not different, other than left main trunk stenting being more frequent in the FKI group. We therefore believe that comparison of arterial responses using these retrospective observational data can still offer valid information, and the true impact of FKI will be explored in subsequent randomized clinical trials currently being planned. Prevalence of Jailing Struts at the Side-Branch Orifice We observed the side-branch orifice in detail on OCT, and clearly identified jailing struts at the side-branch orifice and tissue formation surrounding the strut. FKI after the 2-stent technique produces better results than the 2-stent technique without FKI, 13 but few studies have demonstrated the benefit of FKI after single stent placement. A recent report measuring fractional flow reserve in 25 bifurcation PCI showed that FKI increased the fractional flow reserve of the side branch from 0.65±0.08 to 0.85± A phantom model test evaluated on microfocus computed tomography showed the precise condition of the MV and side-branch structures after complex stenting in a 3-dimensional (3-D) bifurcation model. The 3-D view showed a reduction of jailing struts at the side-branch orifice after FKI. 7,15,16 These findings are consistent with the present results, suggesting that FKI reduces the incidence of jailing struts, leading to a decrease in thrombus attachment at stents implanted in de novo coronary bifurcation lesions. Local Determinants of Intra-Stent Thrombus at Bifurcation Although previous studies reported that bifurcation lesions are a risk factor for late stent thrombosis for both bare metal stents and DES, 17,18 the detailed mechanisms of stent thrombosis at bifurcation lesions has not been fully clarified. A recent human autopsy study found a possible association between the existence of uncovered struts without endothelialization and late stent thrombosis OCT-based strut condition and the incidence of thrombus at bifurcation lesions, however, have not been systematically evaluated. A few previous OCT studies found insufficient neointimal coverage of jailing struts at the side-branch orifice, while struts attached to the vessel wall are well covered within the same DES. 9,22 In the present bifurcation study, we observed a higher incidence of subclinical thrombus attachment (28/76 lesions, 36.8%) than has been reported for non-bifurcation lesions. 8 Also, the incidence of thrombus attachment at the side-branch orifice was significantly lower in the FKI group than in the non-fki group. These findings imply the following: (1) the presence of jailing struts hanging over the side-branch ostium could accelerate thrombus formation by reducing homogeneous strut coverage and arterial healing of the bifurcation lesions; and (2) FKI may protect the orifice of the side branch against thrombus formation after single stenting of bifurcation lesions by decreasing the number of jailing struts susceptible to remaining uncovered and thrombus attachment, even in the late phase. Indeed, the incidence of uncovered struts at the side-branch orifice was significantly higher than that in the vessel walls adjacent to and opposite from the ostium. Also, a recent angioscopy study by Kotani et al showed that thrombus formation is associated with incomplete strut coverage in DES. 23 These findings support the present speculation. Regarding the malapposed struts at bifurcation segment, the incidence of malapposed struts at the AO and OO segments were not statistically different between the FKI and non-fki groups. The numbers and proportions of malapposed struts were, however, almost double (AO: FKI group, 9.1% 3/33 vs. non-fki group, 16.3% 7/43, P=0.36; OO: FKI group, 9.1% 3/33 vs. non-fki group, 18.6% 8/43, P=0.24). Because this study is based on a limited number of patients, the study might have insufficient power to detect the difference between the 2 groups at bifurcation segment. Another explanation for this might be structural deformation induced by FKI. Guerin et al found that the deformations of stent struts occurred during the FKI procedure. 24 Because bifurcation lesions have complicated 3-D structure, the malapposed struts of the AO and OO lesions might still remain after FKI. QCA showed that the MLD of the MV proximal segment after PCI was larger in the FKI group than in the non-fki group. OCT showed that stent expansion in the proximal crosssection was larger, but more elliptical (low stent eccentricity index) in the FKI group than in the non-fki group. Oval stent expansion may induce heterogeneous drug-elution and increase turbulent coronary flow, which theoretically could increase the chance of thrombus formation, 8 although there was no difference in the frequency of thrombus attachment at the proximal segment between the FKI and non-fki groups. In the present study, the frequency of stent malapposition among struts other than those at the side-branch orifice was lower after FKI for the side branch of the proximal segment. Also, OCT showed more frequent uncovered stent struts in the non-fki group at the proximal and distal segments, as well as at the AO and OO

8 1200 HARIKI H et al. sites, of the bifurcation segment than in the FKI group. The balloon:artery ratio was significantly different between the 2 groups, because of the differences of maximum balloon diameter. At distal MV, the balloon:artery ratio was relatively higher in the FKI group. These adequate expansions of implanted stents might be effective for better apposition and might influence the lower frequency of malapposition at the proximal MV and the lower percentage of uncovered struts at the distal and proximal segments in the FKI group compared to non-fki group. Although FKI might induce more elliptical stent expansion than non-fki at the proximal segment, more aggressive stent expansion with FKI might have an advantage in reducing the number of uncovered struts by achieving better strut apposition to the vessel wall, thereby counterbalancing the ovalshaped expansion, which may lead to thrombus formation. The present results suggest that FKI has a potential long-term benefit by reducing the number of uncovered struts at sites other than the side-branch ostium, leading to protective effects against very late stent thrombosis. A large-scale prospective randomized study with longer follow-up is necessary to further validate this speculation. Difference Between SES and PES It is possible that the DES type also affects the vascular response. In the present study, the frequency of thrombus was 38.8% (19/49 stents) in SES and 33.3% (9/27 stents) in PES. On OCT the percentage of uncovered struts was not different between the SES and PES groups in the distal (8.9±13.3% vs. 7.4±8.2%, P=0.60), proximal (10.7±11.6% vs. 8.2±10.2%, P=0.35), and bifurcation (8.8±10.6% vs. 9.5±6.6%, P=0.73) segments. In the FKI group, PES had a significantly lower %jailing struts than SES (3.0±3.7% vs. 7.2±6.7%, P<0.01), suggesting better expansion capacity for PES than SES at the side-branch ostium. Balloon:artery ratio was similar between SES and PES groups (SES, 1.07±0.19 vs. PES, 1.02±0.16; P=0.49). These results seem to be consistent with a previous report that stent type was not an independent predictor of thrombosis. 25 Clinical Outcome A previous study noted a similar clinical outcome between lesions treated with MV stenting with and without FKI. The Nordic-Baltic Study III showed that main branch stenting in coronary bifurcation with and without FKI had a similar 6-month clinical outcome, including MACE (cardiac death, myocardial infarction, TLR, definite stent thrombosis) rates (2.1% in the FKI group and 2.5% in the non-fki group). Although the present 8-month angiographic follow-up found a lower rate of binary restenosis in the FKI group, the present study might be underpowered to demonstrate a clear clinical benefit of FKI considering the observed low event rate. Another study found a similar incidence of angiographic restenosis at the side branch and MACE between SES- and PES-implanted bifurcation lesions with FKI. 26 These data suggest that the side branch is prone to angiographic restenosis following main branch stenting but, even though FKI can reduce the incidence of side-branch restenosis, clear clinical benefit of FKI has not been fully elucidated. In the present study the MACE and TLR rates were also equivalent between the FKI and non-fki groups, while angiographic restenosis at the side branch was higher in the non- FKI group than the FKI group (FKI group, 24.2%; non-fki group, 58.1%, P=0.003). From OCT findings, the frequencies of jailing strut and thrombus attachment were significantly lower in the FKI group than the non-fki group, which may have contributed to the lower incidence of angiographic restenosis of the side branch in the FKI group. The present TLR rate was relatively high (9.1% in the FKI group and 9.3% in the non-fki group) compared with the Nordic-Baltic Study III. 6 The present study evaluated only true bifurcation lesions, and baseline QCA showed that the present patients had a greater severity of stenosis lesions. In general, the tissue distribution, carina shift, and plaque shift more frequently accompany severe stenosis lesions. Therefore, we speculate that the difference in the baseline lesion severity might explain the present relatively high TLR rate compared with that in the Nordic-Baltic Study III. Study Limitations This study had several limitations. First, the sample size was relatively small despite the large number of cross-sections and struts analyzed, which affects the association between the OCT results and the clinical outcome, raising the possibility of selection bias. An angioscopy-controlled study or serial OCT analysis is required to further confirm the present results. Second, the study was an observational retrospective study, therefore it is still unclear whether FKI to ensure optimal stent apposition could further reduce the incidence of thrombus formation in patients receiving DES at the bifurcation lesion. Also, the present results should be interpreted cautiously and as hypothesis generating. Third, because we did not perform OCT immediately after PCI, it is unclear whether malapposed struts observed on follow-up OCT occurred immediately after PCI (residual) or appeared during follow-up (late acquired). We, however, performed the index procedure under IVUS guidance for all of the present patients and verified that there was no malapposition immediately after PCI. Also, considering the relatively low incidence of late-acquired malapposition after SES implantation (1.5%: 108/73,929 struts on OCT), 27 we currently consider that most of the present observed malapposed struts were residual, and mainly caused by the stenting procedure. OCT definition of thrombus at the bifurcation segment has not been validated because blooming and shadow of the struts may occasionally interfere with recognition of the tissue attached to the stent strut. Fourth, this study examined only SES and PES without any comparison to bare metal stents or other DES. Finally, the study design was observational; therefore, it remains unclear whether FKI to acquire optimal stent apposition could further reduce the incidence of thrombus formation in patients receiving DES at bifurcation lesions. Conclusion FKI may reduce the frequency of subclinical thrombus, especially at the side-branch orifice, possibly through the reduction of jailing struts. This may have a potential long-term benefit in the setting of single DES stenting of bifurcation coronary lesions, although the presence of a thrombus did not increase the risk of MACE in this small cohort. Disclosure: nothing to disclose. References 1. 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