Deutsches Herzzentrum München and 1. Klinikum rechts der Isar, Technische Universität, Lazarettstrasse 36, Munich, Germany

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1 European Heart Journal (2008) 29, doi: /eurheartj/ehn512 CLINICAL RESEARCH Interventional cardiology Culotte stenting technique in coronary bifurcation disease: angiographic follow-up using dedicated quantitative coronary angiographic analysis and 12-month clinical outcomes Tom Adriaenssens *, Robert A. Byrne, Alban Dibra, Raisuke Iijima, Julinda Mehilli, Olga Bruskina, Albert Schömig, and Adnan Kastrati Deutsches Herzzentrum München and 1. Klinikum rechts der Isar, Technische Universität, Lazarettstrasse 36, Munich, Germany Received 17 March 2008; revised 21 September 2008; accepted 23 October 2008; online publish-ahead-of-print 11 November 2008 This paper was guest edited by Prof. Christiaan J.M. Vrints, Department of Cardiology, University of Antwerp-University Hospital Antwerp, Belgium. See page 2831 for the editorial comment on this article (doi: /eurheartj/ehn385) Aims Percutaneous treatment of coronary bifurcation disease remains challenging. In patient subsets in which a two-stent strategy is necessary, the culotte technique is a widely used method. We sought to examine the clinical and angiographic outcomes of patients treated in this manner at our institution. As quantitative coronary angiographic analysis using standard measurement programmes is problematic, we used a dedicated bifurcation analysis system.... Methods We prospectively enrolled patients undergoing culotte stenting with drug-eluting stents (Cypher, Endeavor, polymer-free and results rapamycin-eluting, Taxus) in two German centres. Lesions were classified according to the Medina classification. Angiographic follow-up was scheduled between 6 and 12 months post-index procedure. Clinical follow-up was available up to 12 months. Culotte technique was used in 134 lesions in 132 patients. Of these, 124 (92.5%) represented true bifurcation lesion morphology. Kissing balloon inflation was used in 62% of patients. Procedural angiographic success was achieved in all lesions. Follow-up coronary angiography was performed in 108 (81.8%) patients. Median (IQR) late lumen loss was 0.10 ( ) mm in the proximal main vessel, 0.34 ( ) mm in the distal main branch, and 0.30 ( ) mm in the side branch. The incidence of binary angiographic restenosis was 22% for the whole bifurcation lesion, 0% in the proximal main vessel, 9.1% in the distal main branch, and 16% in the side branch. At 12 months, 28 of 132 (21%) patients had undergone target lesion revascularization. The incidence of stent thrombosis (at 1 year) was 1.5%. Predictors of angiographic restenosis were older age, increasing bifurcation angle, more severe distal main branch stenosis, and smaller side branch reference diameter; kissing balloon post-dilatation tended to have a protective effect.... Conclusion The culotte stenting technique is associated with high procedural success and a relatively low risk of angiographic restenosis. Safety results in our cohort were favourable in terms of a low risk of stent thrombosis Keywords Bifurcation Double-stenting technique Culotte technique Percutaneous coronary intervention In-stent restenosis Stent thrombosis Quantitative coronary angiography Introduction Coronary bifurcation disease remains one of the complex coronary lesion subsets that pose a challenge for the interventional cardiologist. The percutaneous treatment of bifurcations is common, accounting for 15 20% of interventions. 1,2 When compared with non-bifurcation interventions, bifurcation interventions have a lower rate of procedural success, higher procedural costs, Present address. University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. * Corresponding author. Tel: þ , Fax: þ , tom.adriaenssens@uzleuven.be Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oxfordjournals.org.

2 Culotte stenting technique in coronary bifurcation disease 2869 longer hospitalization, and a higher rate of clinical and angiographic restenosis. The introduction of drug-eluting stents has resulted in a lower event rate and reduction of main vessel restenosis, however side branch ostial residual stenosis and long-term restenosis remain a problem. 3 6 Furthermore, bifurcation intervention represents one of the independent risk factors for stent thrombosis in several analyses Recent randomized comparisons between single- or double-stent techniques did not find that stenting the side branch decreases restenosis rate, thus providing support for a provisional side branch stenting strategy where possible. However, one possible explanation for this may be the fact that using the one-stent technique may actually represent a selection bias for less complex lesions while more complex lesions need to be treated with two stents. The high cross-over rate between the single-stent and the double-stent group in most of these studies underscored the need for safe and reliable double-stent techniques. In recent years, several fundamentally different double-stent techniques have been described, the most widely adopted being T-stenting technique, crush technique, culotte technique, V and kissing stent technique. The culotte technique is a widely used method though there is a notable absence of published data on outcomes of patients treated in this manner. We therefore undertook an examination of the clinical and angiographic outcomes of patients treated with the culotte technique at our institution. As quantitative coronary angiographic (QCA) analysis using standard measurement programmes is problematic, we used a dedicated bifurcation software system for our angiographic analyses. Methods Study population This prospective, observational study collected information on patients undergoing culotte stenting in two German centres, the Deutsches Herzzentrum München and Klinikum rechts der Isar, both in Munich, Germany, between June 2003 and December Bifurcation interventions in the left main coronary artery were excluded from the current analysis, since they are part of a larger, randomized trial. All cases involving culotte stenting were included, both in situations where the culotte technique was the outset strategy as well as the de facto outcome following on from a provisional main-vessel-only stenting strategy. The demographic data, patient history, coronary risk factors, lesion location, morphology, and procedural strategy were recorded. All patients provided written informed consent. Procedures and intervention medications The culotte technique consists of stenting one of two branches of the bifurcation lesion first, and after balloon dilatation of the stent meshes, stenting the uncovered branch through the first stent and leaving the proximal main vessel covered with two overlapped stents. 11 Ideally, the procedure is terminated by kissing balloon dilatation of both branches, though this was at the discretion of the operator. Aspirin and unfractionated heparin were administered per standard practice. The use of IIb/IIIa inhibitors was left at the discretion of the operator. After the procedure, patients were maintained on aspirin 100 mg twice daily indefinitely, and clopidogrel 75 mg twice daily until discharge and 75 mg daily for at least 6 months. Other medicaments such as b-blocker, statins, and angiotensin converting enzyme inhibitors were given as indicated. After enrolment, patients remained at hospital for at least 48 h. Electrocardiograms were recorded and blood was collected for determination of creatine kinase and its MB isoenzyme before intervention, and every 8 h for the first 24 h after intervention and daily until hospital discharge. Qualitative and quantitative angiographic evaluation All bifurcation lesions were classified according to the Medina classification (Table 3), a relatively new classification, 12,13 in which a binary value (1,0) is given, according to whether the parent vessel proximal to the bifurcation, the main branch distal to the bifurcation or the side branch is compromised (1) or not (0). Procedural angiographic success was defined as a post-procedural final residual stenosis,30% by visual analysis in the presence of Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 without death, occurrence of Q-wave myocardial infarction (MI), or coronary bypass graft surgery (CABG). Between 6 and 12 months after the index procedure, all patients were invited back for angiographic follow-up. Coronary angiograms were obtained in multiple views after intracoronary injection of nitrates. QCA analysis was performed with the dedicated bifurcation system QAngio XA 7.1 (MEDIS, Leiden, The Netherlands). This new program analyses the main vessel and side branch in one single analysis. 14 A minimal cost algorithm detects the contours of the proximal main vessel, distal main branch and side branch. The lesion is then divided into four fragments: a central fragment at the actual location of the bifurcation, and three fragments around the bifurcation. Each of the individual vessel fragments are combined with the central fragment to form three segments, so the actual bifurcation is taken into account in all three individual measurements. The reference vessel diameter, minimal lumen diameter (MLD), and percent diameter stenosis were measured pre- and post-procedurally and at follow-up angiography. The late lumen loss was calculated as the difference between the post-procedure and follow-up MLD for each of the three segments. Binary restenosis was defined as the presence of.50% diameter stenosis within the target lesion. The binary restenosis rate was also calculated for the entire bifurcation lesion. The angiographic pattern of in-stent restenosis (ISR) was further classified according to the classification proposed by Mehran et al., 15 with pattern I including focal (,10 mm in length) lesions, pattern II.10 mm within the stent, pattern III.10 mm extending outside the stent, and pattern IV totally occluded ISR. Pattern I ISR was further subdivided into Type I A (articulation or gap), Type I B (margin), Type I C (focal body), and Type I D (multifocal). All lesions were also classified according to the bifurcation angle (BA) defined as the angle between the axis of the distal main vessel and the axis of the side-branch at its origin (in contradistinction to the access angle, which represents that angle subtended by the proximal main vessel and the side branch). The measurement was performed in the angiographic view with least foreshortening of the three segments, usually the operator s working view and the view in which QCA measurements were done. The study population was divided using the median BA (528) as the cut point into a low-angle group (BA,528) and a high-angle group (BA.528). Clinical definitions and follow-up Clinical follow-up by phone contact or office visit was obtained at 1 and 12 months and evaluated the rate of death, acute MI (AMI), or target lesion revascularization (TLR). The diagnosis of MI required the presence of new Q-waves in the electrocardiogram and/or

3 2870 T. Adriaenssens et al. elevation of creatine kinase or its MB isoenzyme at least three times the upper limit of normal in at least two blood samples. TLR was defined as either surgical or percutaneous reintervention driven by significant (.50%) luminal diameter narrowing either within the stent or the 5 mm borders proximal and distal to the stent and was undertaken in the presence of either anginal symptoms or objective evidence of ischaemia. Stent thrombosis was assessed based on the definitions of the Academic Research Consortium (ARC) into definite, probable, or possible stent thrombosis. 16 Stent thrombosis was also categorized according to the timing of the event into: intra-procedural, early (between 0 and 30 days after the index procedure), and late (.30 days after the index procedure). Statistical analysis Discrete variables are presented as numbers (percentages). Continuous variables are expressed as median (IQR) or mean+standard deviation. Confidence intervals for incidences were calculated using the Poisson exact method. A logistic regression model was established to investigate independent predictors of restenosis. Based on prior clinical trial experiences the following clinical variables were chosen as likely meaningful variables and only these were entered into the analysis model as explanatory variables: age, diabetes, gender, Medina classification, restenotic lesion, angle of bifurcation, calcified lesion, reference diameter of the proximal main vessel, stenosis of the proximal main vessel, reference diameter of the distal main branch, stenosis of the distal main branch, reference diameter of the side branch, stenosis of the side branch, and kissing balloon postdilatation (KBP). Explanatory variables were assumed to be independent and error-free. The model was assessed for goodness-of-fit using R 2. All tests were two-sided unless explicitly indicated and a P-value of,0.05 was considered statistically significant. Formal correction to account for multiple testing was not employed. Results The culotte stenting procedure was the dominant two-stent strategy at our institution during the study time period. Of 1103 treated lesions where a coronary bifurcation was involved, 422 required intervention in both the main vessel and side branch (252 balloon angioplasty in the side arm, 36 non-culotte 2-stent interventions, and 134 culotte interventions). The 134 culotte treated lesions occurred in 132 patients. In these 132 patients, a total of 239 lesions were treated with DES during the index intervention, including 105 non-bifurcational lesions which are not analysed here. The overall mean number of lesions treated per patient was Baseline patient characteristics are listed in Table 1. Median patient age was 65.5 (57.9, 73.1) years. Patients underwent percutaneous coronary intervention because of stable coronary heart disease in 61.4%, unstable angina pectoris/non-st-elevation myocardial infarction (NSTEMI) in 32.6%, and STEMI in 6.1%. Baseline angiographic and procedural characteristics are shown in Table 2. The target bifurcation lesion was the left anterior descending/diagonal branch in 91 patients, left circumflex/obtuse marginal branch in 30, and distal right coronary artery in 13 of the 134 lesions. Two patients had two bifurcation lesions stented during the same intervention. Defined according to the Medina classification (1,1,1), (1,0,1) or (0,1,1), 124 (92.5%) lesions represented a true bifurcation lesion morphology (Table 3). Four different types of drug-eluting stents were implanted. The Cypher sirolimus-eluting Table 1 Baseline demographic and clinical characteristics of the patients Variable Patients (n ¼ 132) Age, years Women, n (%) 30 (22.7) Diabetes mellitus, n (%) 22 (16.7) Current smoker, n (%) 19 (14.4) Arterial hypertension, n (%) 88 (66.7) Hypercholesterolaemia, n (%) 87 (65.9) Single-vessel disease 34 (25.8) Multivessel disease 98 (74.2) Stable angina, n (%) 81 (61.4) Unstable angina/non-st elevation myocardial 43 (32.6) infarction, n (%) Acute myocardial infarction, n (%) 8 (6.1) Prior myocardial infarction, n (%) 37 (28.0) Prior aortocoronary bypass surgery, n (%) 8 (6.1) Left ventricular ejection fraction, % Data are presented as mean+sd or number (percentages). stent in 45 lesions (33.6%), the Taxus paclitaxel-eluting stent in 27 (20.1%), the Endeavor zotarolimus-eluting stent in 7 (5.2%), and the polymer-free rapamycin-eluting stent in 55 (41%) of lesions. 17 Procedural angiographic success was achieved in all lesions. Clinical outcomes Clinical follow-up data at 12 months were available in all patients included in the study (Table 4). Twenty-six of 132 (19%) patients underwent TLR. The incidence of stent thrombosis (at 1 year) was 1.5% (one patient suffered stent thrombosis 40 days after the procedure, 1 week after he had stopped clopidogrel treatment; the other patient suffered stent thrombosis 47 days after the procedure, while on dual antiplatelet therapy). According to the ARC criteria, both stent thromboses were classified as definite and late (occurring between 30 days and 1 year after the procedure). There were no probable or possible stent thromboses and no periprocedural or early stent thromboses (occurring between 0 and 30 days post intervention). There were no deaths and the incidence of MI at 1 year follow-up was 8.2%. Of the 10 cases of MI during 12- month clinical follow-up, two were caused by stent thrombosis (one NSTEMI, one STEMI), both of which were treated successfully with balloon dilatation. There were two other NSTEMI (one subtotal occlusion in a vessel distal to the bifurcation lesion and another subtotal occlusion in a vessel other than the initial bifurcation lesion). Both were treated successfully with percutaneous intervention. The others were small peri-interventional MIs with only minimal enzyme elevation. Quantitative angiographic analysis Follow-up coronary angiography was performed in 108 (81.8%) patients. Data from control angiography after 6 8 months are

4 Culotte stenting technique in coronary bifurcation disease 2871 Table 2 Angiographic and procedural data Variable Lesions (n ¼ 134) Target vessel Left anterior descending coronary artery, n (%) 91 (67.9) Left circumflex coronary artery, n (%) 30 (22.4) Right coronary artery, n (%) 13 (9.7) Complex (type B2/C) lesions, n (%) 126 (94.0) Chronic total occlusions, n (%) 4 (3) In-Stent restenosis lesion, n (%) 21 (16) Calcified lesions, n (%) 96 (71.6) Baseline vessel size, mm Proximal main vessel 3.02 (2.85, 3.30) Distal main branch 2.79 (2.48, 2.96) Side branch 2.50 (2.32, 2.74) Initial minimal lumen diameter, mm Proximal main vessel 1.86 (1.33, 2.44) Distal main branch 1.12 (0.90, 1.58) Side branch 1.09 (0.75, 1.47) Initial diameter stenosis, % Proximal main vessel 38.9 (18.9, 57.2) Distal main branch 56.9 (46.0, 67.2) Side branch 55.9 (41.9, 70.8) Lesion length, mm Proximal main vessel 5.50 (3.44, 7.75) Distal main branch 8.32 (5.5, 12.8) Side branch 8.13 (5.83, 11.6) Maximal balloon pressure, atm Main vessel 15.0 (12.0, 17.0) Side branch 16.0 (12.0, 17.0) Stent diameter, mm Main vessel a Side branch a Stent length, mm Main vessel 23.0 (18.0, 28.0) Side branch 18.0 (16.0, 25.0) Type of DES implanted Cypher 45 (33.6) Endeavor 7 (5.2) Polymer-free rapamycin-eluting 55 (41) Taxus 27 (20.1) Minimal lumen diameter after procedure, mm Proximal main vessel 2.98 (2.70, 3.23) Distal main branch 2.42 (2.15, 2.72) Side branch 2.14 (1.96, 2.42) Diameter stenosis after procedure, % Proximal main vessel 4.3 (1.0, 9.5) Distal main branch 12.5 (8.1, 21.4) Side branch 15.8 (9.0,24.4) Kissing balloon post-dilatation, n (%) 83 (62.0) Data are presented as median (IQR) or number (percentages). a Indicates range provided rather than median (IQR). Table 3 Medina classification of the lesions Variable Lesions, n ¼ 134 (%) 0,0,1 2 (1.5) 0,1,0 5 (3.7) 1,0,0 0 (0) 0,1,1 27 (20.2) 1,0,1 7 (5.2) 1,1,0 3 (2.2) 1,1,1 90 (67.2) Data are presented as number (percentages). The components of the three-digit score refer to the proximal main vessel, distal main vessel, and side branch vessel, respectively. 12 Table 4 Clinical outcomes of the patients Outcome Number of Percentage (CI) a patients, n Target lesion revascularization ( ) at 30 days Stent thrombosis at 30 days (0.03) b Death at 30 days (0.03) b Myocardial infarction at ( ) days Death or myocardial infarction ( ) at 30 days MACE at 30 days ( ) Target lesion revascularization ( ) at 1 year Stent thrombosis at 1 year ( ) Death at 1 year (0.03) b Myocardial infarction at 1 year ( ) Death or myocardial infarction ( ) at 1 year MACE at 1 year ( ) a CI, Poisson exact confidence intervals. b One-sided 97.5% confidence interval. presented in Table 5. Late lumen loss was mm in the proximal main vessel, mm in the distal main branch, and mm in the side branch. The incidence of binary angiographic restenosis at 6 months was 22% for the whole bifurcation lesion, 0% in the proximal main vessel, 9.1% in the distal main branch, and 16% in the side branch. With regard to the angiographic pattern of restenosis, restenotic lesions in the main vessel (n ¼ 10) occurred only in the part distal to the bifurcation point, with five classified as pattern I C (focal body), 1 pattern I D multifocal, and 4 pattern II (diffuse intrastent). Of restenotic lesions in the side branch (n ¼ 18), there were seven pattern I C (focal body; five of which at the ostium), seven pattern II (diffuse intrastent), two pattern III (diffuse proliferative), and two pattern IV (total occlusions). We tried to identify predictors of restenosis after culotte DES bifurcation intervention and examined the impact of the severity

5 2872 T. Adriaenssens et al. Table 5 Quantitative coronary angiography Variable Lesions (n ¼ 134) Late lumen loss in-stent, mm Proximal main vessel 0.10 (20.04, 0.38) Distal main branch 0.34 (0.03, 0.66) Side branch 0.30 (20.01, 0.72) Minimal lumen diameter in-stent, mm Proximal main vessel 2.83 (2.51, 3.12) Distal main branch 2.08 (1.84, 2.42) Side branch 1.81 (1.53, 2.12) Diameter stenosis in-segment, % Proximal main vessel 8.6 (1.7, 15.3) Distal main branch 24.5 (41.1, 34.6) Side branch 28.0 (18.7, 40.2) Angiographic restenosis in-segment, n (%) Bifurcation lesion 24 (22.0) Proximal main vessel 0 Distal main branch 10 (9.1) Side branch 18 (16.0) Data are presented as median (IQR) or number (percentages). of the baseline lesion (expressed via the Medina classification), the angle between main branch and side branch and the use of KBP or not. It appeared that the more severe bifurcation lesions, with Medina score (0,1,1), (1,0,1), (1,1,0) and the most severe lesions with Medina score (1,1,1) had a clearly elevated restenosis risk of 29 and 20.3%, respectively, where no restenosis was seen in the very small number of patients with less complex bifurcation lesions with Medina score (0,0,1), (0,1,0), and (0,0,1). As to the use of KBP, restenosis occurred in 11 of 71 (15.5%) of patients with vs. 13/39 (33.3%) of patients without KBP. With respect to the angle of the bifurcation lesion, an angle over the mean of 528 correlated with a higher rate of restenosis (13 of 54 or 24.1% of lesions) compared with lesions with smaller BAs,528 (restenosis in 11 of 56 or 19.6% of lesions). There was a numeric trend towards an excess of restenosis with Endeavor and Taxus stents though an interaction between stent type and binary restenosis rates was not statistically significant [Cypher 7 (18.0%), Endeavor 2 (28.6%), polymer-free rapamycin-eluting 6 (15.8%), Taxus 9 (34.6%); P ¼ 0.12]. By logistic regression analysis (see Table 6), the predictors for angiographic restenosis were older age, increasing BA, more severe stenosis in the distal main branch, and a smaller reference diameter of the side branch. The use of KBP seemed to have a protective effect on the occurrence of restenosis in the bifurcation lesion, although not statistically significant (odds ratio 0.37; 95% CI ; P ¼ 0.07). Discussion The strengths of this report are that it is the largest report on the use of culotte technique with DES and the largest report on the Table 6 Logistic regression model Variable Odds ratio (95% CI) P-value Age increase by 10 years 2.38 ( ) 0.01 Diabetes 3.43 ( ) 0.13 Male sex 0.62 ( ) 0.51 Medina classification 0.42 ( ) 0.14 Restenotic lesion 0.52 ( ) 0.38 Bifurcation angle increase by ( ) 0.03 Calcified lesion 0.53 ( ) 0.39 Proximal main vessel Reference vessel diameter decrease by 1 mm Baseline stenosis increase by 10% 0.91 ( ) 0.54 Distal main vessel Reference vessel diameter decrease by 1 mm Baseline stenosis increase by 10% 1.47 ( ) 0.03 Side branch vessel Reference vessel diameter decrease by 1 mm Baseline stenosis increase by 10% 0.97 ( ) 0.75 Kissing balloon post-dilatation 0.37 ( ) 0.07 Predictors of binary restenosis. CI, confidence interval. use of a dedicated bifurcation QCA system for angiographic analysis. It shows that the culotte technique is associated with favourable safety outcomes in terms of a low risk for stent thrombosis. While the risk of restenosis remains significant compared with more straightforward DES interventions, this may be regarded as acceptable considering the lesion complexity. In addition, while previous reports have identified predictors of restenosis in bifurcation interventions, this is the first report to do so for the culotte technique and indicates that completing the procedure with KBP could be associated with better long-term results. Bifurcation approaches 4.55 ( ) ( ) ( ) 0.02 The optimal treatment strategy for coronary bifurcation lesions remains to be defined. There is consensus that drug-eluting stents are superior to bare metal stents in this lesion subset. 17 Recent studies lend support to a strategy of provisional side branch stenting when confronted with the need for coronary bifurcation intervention. 18,19 However, there is agreement among many interventional cardiologists that in several situations (e.g. severe ostial disease of the side branch, dissection or diminished flow, a large territory at risk in the side branch etc.), there is need for a safe and reliable double-stenting technique. In this regard, different technical options are available to the operator. The T-stenting technique is limited by a need for extremely precise stent positioning to ensure complete coverage of the side branch ostium. An alternative technique, crush stenting, is relatively easy to perform, though KBP is mandatory to achieve acceptable rates of restenosis of the side branch. 20,21

6 Culotte stenting technique in coronary bifurcation disease 2873 The culotte technique has several major advantages. First, it allows the operator to start the intervention using a provisional side branch stenting approach. The culotte technique offers the advantage over the crush technique of having only two and not three stent layers in the proximal part of the bifurcation lesion, potentially leading to a lower risk of incomplete stent apposition. From a technical point of view, final re-wiring into the side branch, with the aim of performing KBP, is easier after culotte than after crush stenting. Finally, the result after properly performed culotte stenting and KBP leads to optimal bifurcation coverage, least recoil at the ostium site, least residual stenosis, and less stent distortion in comparison with other techniques. These considerations are supported by the work of Ormiston et al. 22 in a bench testing model of coronary bifurcation interventions. Relatively few outcome data on the culotte technique are available in the literature. It was first described one decade ago, 11 before the advent of drug-eluting stents, though only two small studies report on the culotte technique in the DES era. Hoye et al. 23 report on 24 lesions, with no cases of stent thrombosis, and one repeat revascularization procedure at 8 month follow-up. In this series of lesions, late loss was 0.48 mm for the main vessel and 0.53 mm for the side branch. Kaplan et al., 24 performed a nonrandomized comparison in a limited number of patients (n ¼ 80), between the culotte technique and the T-stenting technique. In the group of patients treated with culotte stenting, 45 in total, TLR rate was 8.9% while stent thrombosis occurred in only one patient (2.2%). Interestingly, the culotte technique yielded significantly better immediate angiographic result at the side branch ostium, and better clinical outcomes at 9 months, when compared with T-stenting. Stent thrombosis Since there are no published randomized trials comparing different double-stent techniques for the treatment of coronary bifurcation lesions, one can only compare the results of the current study with historical controls of other treatment strategies. In particular, recent data on outcomes of patient cohorts treated with the crush technique using DES has raised concern regarding rates of stent thrombosis with bifurcation stenting. Analysing 241 lesions, Hoye et al. 25 noted a stent thrombosis rate at 9 months of 4.3%. In a smaller number of patients, Ge et al. 20 reported a stent thrombosis rate (combined intra-procedural and post-procedural) of 3.5% at 9 months. Costa et al. 26 suggest an association between incomplete apposition of crushed stent struts against the main vessel wall and the development of stent thrombosis as a possible explanation. The most extensive information on T-stenting with drug-eluting stents was published by Colombo. 4 He compared a single stent (22 lesions) with a double-stent strategy (60 of 63 lesions treated with T-stenting technique). At 6 months, the incidence of stent thrombosis was 4.8%, when one sudden death was also considered, the combined incidence of sudden death and stent thrombosis rose to 6.3% in the double-stent group. Conversely, a later paper from the same group compared crush and T- stenting techniques and reported lower rates of stent thrombosis in the T-stenting group (3.3 vs. 0%). 21 Our incidence rate (at 1 year) utilizing ARC criteria was notably lower at 1.5% and more in keeping with the two smaller culotte series previously discussed. 23,24 Superior stent apposition with the culotte technique (in comparison with crush and t-stenting) is a possible explanation. The absolute numbers of stent thrombosis events in all studies are in fact very small, and the validity of comparison between these heterogeneous patient groups is limited. Nevertheless, given the huge impact on morbidity and mortality of stent thrombosis, these differences may have clinical relevance and warrant further investigation. Although, a specific analysis of the length of stent overlap in this current study is not available, the discrepancy between lesion length and stent length as reported in Table 2 can be interpreted as evidence of considerable proximal main vessel stent overlap an inherent technical characteristic of the culotte technique, which may be postulated to optimize stent apposition and coverage at the carina. Whether the resultant DES double-layer results in significant differences with respect to drug dosing effects compared with the triple-layer coverage seen with the crush technique is not known. Anti-restenotic efficacy In terms of anti-restenotic efficacy, late lumen loss and restenosis rates in main vessel and side branch in our patient population compare well to the results of these historical controls (Figure 1). 4,20,21,23,24 While rates of re-intervention on the target lesion remain significant (21% at 1 year), this may be regarded as acceptable in a high-risk patient cohort 67.7% of lesions being classified as Medina (1,1,1), 74.2% of patients having multivessel disease, and 16% of lesions being ISR lesions. The presence of AMI, severely depressed left ventricular function or renal insufficiency were not exclusion criteria for our analysis. In comparison with the other reports, our study has the longest clinical follow-up (12 months compared with only 6 or 9 months in most of the other series). In terms of predictors of reduced anti-restenotic efficacy, our study confirmed the previously reported negative impact of a higher BA. 27 It is hypothesized that the achievement of an effective post-dilatation of the side branch may be more challenging as the BA approaches 908, resulting in some degree of side branch or main vessel stent underexpansion. 28 The overall relatively high residual stenosis in the side branch post-intervention (median 15.8%, IQR %) may also be consistent with a degree of ostial side branch stent deformation in certain cases and is in keeping with the fact that no two-stent technique can completely eliminate excess metal from the carina. In line with several reports on crush stenting, 20,25 our study demonstrated a beneficial effect of KBP on restenosis (total restenosis rate of 33% in lesions without KBP vs. 15% in lesions treated with KBP). Quantitative coronary angiography Conventional QCA algorithms are designed to detect vessel contours assuming minimal vessel tapering. Since there is, also in the non-diseased state, a step down in the reference diameter of the main vessel from proximal to distal and from main vessel to side branch, the reference vessel dimensions measured with these standard algorithms are inherently inaccurate when applied to bifurcation lesions. Because the percentage diameter stenosis is derived from the reference diameter, the percentage diameter stenosis of a bifurcation lesion will be either underestimated or overestimated as a result of the systematic errors in reference

7 2874 T. Adriaenssens et al. Figure 1 The culotte technique for coronary bifurcation stenting. (A) Baseline angiogram with significant stenosis of the left anterior descending (LAD)/second diagonal bifurcation. (B) After wiring and pre-dilatation of both vessels, a first stent is positioned in the LAD, overstenting the ostium of the side branch. (C) The wire is removed from the LAD, the stent is crossed with this wire into the diagonal branch which is then dilated. (D) The second stent is then positioned covering the whole lesion in the diagonal branch and expanded with overlap in the proximal vessel (LAD). (E) After rewiring into the left anterior descending, kissing balloon post-dilatation is performed. (F) Final result. diameter measurement. Furthermore, in the bifurcation lesion, there are different segments of interest that cannot be described by a single measure of percentage diameter stenosis for the entire bifurcation lesion. With the new program, the lesion is divided into four fragments: a central fragment at the actual location of the bifurcation, and three fragments around the bifurcation. Each of the individual vessel fragments is combined with the central fragment to form three segments. This segmental analysis provides a more thorough insight into the precise location of treatment failure or restenosis at follow-up (A. Lansky, personal communication, 2007). In a comparison with the use of the conventional and this new QCA software for bifurcation lesions, Goktekin et al. 14 found that the new system could be consistently applied to the analysis of bifurcation lesions before and after angioplasty, with an intra- and interobserver reproducibility equal to or better than the conventional analysis system.

8 Culotte stenting technique in coronary bifurcation disease 2875 Limitations Although our study is the largest to date on culotte stenting, patient numbers remain relatively low. This is a feature of many bifurcation analyses. Meaningful comparison against prior reports on strategies in lesions requiring a two-stent technique is limited both due to the small number of patients, heterogeneity of patient groups and the inherent historical nature of such comparisons. Neither was meaningful comparison against non-culottetreated lesions at our institution available. In addition, a variety of drug-eluting stents, with differing anti-restenotic efficacy, as well as variable strut characteristics and stent cell designs and dimensions (which may be of particular relevance in a through-the-strut two-stent technique such as that described), was used in our study. Conclusions In conclusion, the results of this analysis show that the culotte stenting technique is associated with favourable safety outcomes at 1 year, in terms of a low risk for stent thrombosis. While the risk of restenosis remains significant compared with more straightforward DES interventions, this may be regarded as acceptable in view of the lesion complexity. Completing the procedure with KBP may improve long-term results. In patients requiring intervention with a two-stent technique, a potential safety advantage with the culotte technique in terms of a lower rate of stent thrombosis should be the subject of future investigation. Funding T.A. was supported by a fellowship in interventional cardiology from the European Society of Cardiology. R.A.B. received support from the Irish Board for Training in Cardiovascular Medicine sponsored by A. Menarini Pharmaceuticals (Ireland). 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