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Rationale and design for the treatment effects of systematic two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions (DEFINITION ⅡⅡⅡ Trial)

ForJournal: peerBMJ Open review only

Manuscript ID bmjopen-2017-020019

Article Type: Protocol

Date Submitted by the Author: 10-Oct-2017

Complete List of Authors: Zhang, Junjie; Nanjing First Hospital, Department of Cardiology Gao, Xiaofei; Nanjing First Hospital, Department of Cardiology Han, YL; The General Hospital of Shenyang Military, Department of Cardiology Kan, Jing; Nanjing Heart Center, Department of Cardiology Tao, Ling; Xijing Hospital, 4th Military Medical University, Department of Cardiology Ge, Zhen; Nanjing First Hospital, Department of Cardiology Tresukosol, Damras; Medicine Siriraj Hospital, Mahidol University,

cardiology http://bmjopen.bmj.com/ Lu, Shu; Taicang People‘s Hospital, Department of Cardiology Ma, Likun; Anhui Provincial Hospital, Department of Cardiology Li, Feng; Huainan Eastern Hospital, Department of Cardiology Yang, Song; Yixin People‘s Hospital, Department of Cardiology Zhang, Jun; Cangzhou Central Hospital, Department of Cardiology Munawar, Muhammad; Binawaluya Cardiac Center, Department of Cardiology Li, Li; Guangzhou Red Cross Hospital, Department of Cardiology Zhang, Ruiyan; Shanghai Ruijin Hospital, Department of Cardiology on October 1, 2021 by guest. Protected copyright. Zeng, Hesong; Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Department of Cardiology Santoso, Teguh; Medistra Hospital, University of Indonesia, cardiology Xie, Ping; Gansu Provincial Hospital, Department of Cardiology Jin, Zening; Beijing Anzhen Hospital, Department of Cardiology Han, Leng; Changshu First People‘s Hospital, Department of Cardiology Yin, Wei-Hsian; Cheng-Hsin General Hospital, cardiology Qian, Xuesong; Zhangjiagang First People‘s Hospital, Department of Cardiology Li, Qihua; Changzhou Hospital of Traditional Chinese Medicine, Department of Cardiology Hong, Lang; Jiangxi Provincial People's Hospital, Department of Cardiology Paiboon, Chotnoparatpat; Bangkok General Hospital, cardiology Wang, Yan; Xia‘Men Zhongshan Hospital, cardiology Liu, Lijun; Huainan First People‘s Hospital, Department of Cardiology Zhou, Lei; Jintan People‘s Hospital, cardiology Wu, Xueming; Wuxi Third People 's Hospital, cardiology Wen, Shangyu; Daqing Oil General Hospital, cardiology Lu, Qinghua; The Second Hospital of Shandong University, cardiology Yuan, Junqiang; Xinyang Central Hospital, cardiology

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1 2 3 4 Chen, Lianglong; Fujian Union Hospital, cardiology Lavarra, Francesco; Jilin Heart Hospital, cardiology 5 Rodríguez, Alfredo E. ; Otamendi Hospital, cardiology 6 Zhou, Limin; Chuzhou First People 's Hospital, cardiology 7 Ding, Shiqin; Huainan Xinhua Hospital, cardiology 8 Vichairuangthum, Kitigon; Bangplee Hospital, cardiology 9 Zhu, Yuansheng; Huai‘an Second People‘s Hospital, cardiology 10 Yu, Mengyue; Qingdao Fuwai Hospital, cardiology Chen, Chan; The Affiliated Hospital of Guangdong Medical University, 11 cardiology 12 Sheiban, Imad; Pederzoli Hospital, cardiology 13 Xia, Yong; The Affiliated Hospital of Xuzhou Medical University, cardiology 14 Tian, Yulong; Xuyi People‘s Hospital, cardiology 15 Shang, Zhenglu ; Wuxi Huishan District People‘s Hospital, cardiology 16 Jiang, Qing; Anqing First People‘s Hospital, cardiology For peerZhen, Yonghong; review Liyang Hospital ofonly Traditional Chinese Medicine, 17 cardiology 18 Wang, Xin; Lianyungang Hospital of Traditional Chinese Medicine, 19 cardiology 20 Ye, Fei; Nanjing First Hospital, Department of Cardiology 21 Tian, Nailiang; Nanjing First Hospital, Department of Cardiology 22 Lin, Song; Nanjing First Hospital, Department of Cardiology Liu, Zhizhong; Nanjing First Hospital, Department of Cardiology 23 Chen, Shao-Liang; Nanjing First Hospital, Nanjing Medical University, 24 Department of Cardiology 25 coronary bifurcation lesions, systematic two-stent techniques, provisional 26 Keywords: 27 stenting technique 28 29 30

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1 2 3 Rationale and design for the treatment effects of systematic two-stent and provisional 4 stenting techniques in patients with complex coronary bifurcation lesions 5 6 (DEFINITION ⅡⅡⅡ Trial) 7 8 Jun-Jie Zhang,1 Xiao-Fei Gao,1 Ya-Ling Han,2 Jing Kan,3 Ling Tao,4 Zhen Ge,1 Damras 9 Tresukosol,5 Shu Lu,6 Li-Kun Ma,7 Feng Li,8 Song Yang,9 Jun Zhang,10 Muhammad Munawar,11 10 12 13 14 15 16 17 11 Li Li, Rui-Yan Zhang, He-Song Zeng, Teguh Santoso, Ping Xie, Ze-Ning Jin, Leng 12 Han,18 Wei-Hsian Yin,19 Xue-Song Qian,20 Qi-Hua Li,21 Lang Hong,22 Chotnoparatpat 13 Paiboon,23 Yan Wang,24 Li-Jun Liu,25 Lei Zhou,26 Xue-Ming Wu,27 Shang-Yu Wen,28 Qing-Hua 14 Lu,29 Jun-Qiang Yuan,30 Liang-Long Chen,31 Francesco Lavarra,32 Alfredo E. Rodríguez,33 15 16 Li-Min Zhou,34 Shi-QinFor Ding, peer35 Kitigon Vichairuangthum, review36 Yuan-Shengonly Zhu,37 Meng-Yue Yu,38 17 Chan Chen,39 Imad Sheiban,40 Yong Xia,41 Yu-Long Tian,42 Zheng-Lu Shang,43 Qing Jiang,44 18 Yong-Hong Zhen,45 Xin Wang,46 Fei Ye,1 Nai-Liang Tian,1 Song Lin,1 Zhi-Zhong Liu,1 19 1,3 20 Shao-Liang Chen, * 21 22 Zhang JJ and Gao XF contributed equally to this work. 23 24 25 *Correspondence author: Department of cardiology, Nanjing First Hospital, Nanjing 26 27 Medical University; No. 68 Changle road, 210006 Nanjing, China; Tel & Fax: 28 29 +86-25-52208048; E-mail: [email protected]. 30

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1 2 3 Abstract 4 5 Introduction: Provisional stenting (PS) for simple coronary bifurcation lesions is the 6 7 mainstay of treatment. Systematic two-stent approach is widely used for complex 8 9 bifurcation lesions (CBLs). However, randomized comparison of PS and two-stent 10 11 techniques for CBLs has never been studied. Accordingly, the present study is designed to 12 13 elucidate the benefits of two-stent treatment over PS in patients with CBLs. 14 15 Methods and analysis: The DEFINITION Ⅱ study is a prospective, multinational, 16 For peer review only 17 randomized, endpoint-driven trial to compare the benefits of two-stent technique with PS 18 19 for CBLs. A total of 660 patients with CBLs will be randomized in a 1:1 fashion to receive 20 21 either PS or two-stent technique. The primary endpoint is the rate of 12-month target lesion 22 23 failure (TLF) defined as the composite of cardiac death, target vessel myocardial infarction 24 25 (MI), and target lesion revascularization (TLR). The major secondary endpoints include all 26 27 cause death, MI, target vessel revascularization (TVR), in-stent restenosis, stroke, and each 28 29 individual component of the primary endpoint. The safety endpoint is the occurrence of 30

31 definite or probable stent thrombosis (ST). http://bmjopen.bmj.com/ 32 33 Ethics and dissemination: The study protocol and informed consent have been reviewed 34 35 and approved by the Institutional Review Board at each participating center. The written 36 37 informed consent was obtained from all enrolled patients. Findings of the study will be 38 published in a peer-reviewed journal, and disseminated at conferences. 39 on October 1, 2021 by guest. Protected copyright. 40 Trial registration number: NCT02284750; Pre-results. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 2 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 24 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 Strengths and limitations of this study 4 ‹ This is the first prospective, multinational, randomized, endpoint-driven trial to 5 6 compare the systematic two-stent and provisional stenting (PS) techniques in patients 7 with complex coronary bifurcation lesions (CBLs). 8 9 ‹ This study is built on DEFINITION registry, which for the first time introduced the 10 11 anatomical differentiation of coronary bifurcation lesion’s complexity, and reported 12 that PS for CBLs was associated with an increment of major adverse cardiac events as 13 compared with simple bifurcation lesions. 14

15 16 ‹ Selection of primaryFor and peer secondary review endpoints is in accordance only with the current 17 practice in other cardiovascular clinical trials. 18 19 20 ‹ All participating sites are experienced in two-stent techniques (including DK crush and 21 culotte), which may not be reflective of clinical practice in smaller hospitals. 22 23 24 25 26 27 28 29 30

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1 2 3 Background 4 5 Percutaneous coronary intervention (PCI) of bifurcation lesions is technically demanding 6 7 and poor outcome at follow-up, as reflected by more frequent in-stent restenosis (most 8 localize at the ostium of daughter branch) and more requirements of revascularization. For a 9 10 great majority of coronary bifurcation lesions, particularly when a small (diameter<2.0mm) 11 12 side branch (SB) with focal (usually <5 mm in length) lesions is involved, provisional 13 14 stenting (PS) is considered as the default approach1-6. However, the efficacy of PS for larger 15 16 (≥2.5 mm in diameter)For SBpeer with longer review lesion (>5mm only in length) is under reported7,8. 17 18 Furthermore, there is a lack of angiographical criteria for differentiating simple from 19 20 complex bifurcation lesions (CBLs). In this regard, DEFINITION registry study 9 for the first 21 22 time introduced the anatomical differentiation of bifurcation lesion’s complexity, which 23 24 consisted of 2 major and 6 minor criteria. Based on DEFINITION criteria, CBLs was defined 25 26 as one major plus any two minor criteria. Investigators further reported that PS for CBLs 27 28 was associated with an increment of mortality, ST, and major adverse cardiac events (MACE) 29 and stent thrombosis as compared with simple bifurcation lesions. Unfortunately, PS has not 30 31 been compared with systematic two-stent techniques in a randomized fashion for patients http://bmjopen.bmj.com/ 32 33 with CBLs. Therefore, we designed this prospective, multi-center, randomized (DEFINITION 34 35 ) study to investigate the superiority of systematic two-stent approaches to PS treatment 36 37 for patients with CBLs classified by DEFINITION registry. 38

39 on October 1, 2021 by guest. Protected copyright. 40 41 Study design and methods 42 43 Study hypothesis 44 45 This study is designed to test the hypothesis that the application of systematic two-stent 46 47 techniques will lead to fewer rate of target lesion failure (TLF), including cardiac death, 48 49 target-vessel myocardial infarction (MI), or target lesion revascularization (TLR), compared 50 51 to PS technique in patients with CBLs at 12 months after the indexed PCI procedure. CBLs 52 are defined according to DEFINITION study 9, and the criteria are shown in Table 1. 53 54 55 56 57 4 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 24 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 Study design 4 5 This is a prospective, multi-center, randomized-controlled, superiority trial at up to 45 sites 6 7 worldwide to enroll 660 subjects with CBLs in native coronary artery. The overall study 8 9 flowchart is presented in Figure 1. This study has been registered at clinicaltrials.gov 10 11 (NCT02284750), according to the statement of the International Committee of Medical 12 13 Journal Editors. The study is performed in accordance with the Declaration of Helsinki and 14 15 International Conference on Harmonization of Good Clinical Practices. The study protocol 16 For peer review only 17 and informed consent have been reviewed and approved by the Institutional Review Board 18 19 at each participating center. The written informed consent for participation in the trial was 20 21 obtained from all enrolled patients. 22

23 24 Study population and randomization 25 26 A number of 660 patients scheduled for elective PCI with CBLs suitable for DES implantation 27 28 are openly randomized 1:1 to either systematic two-stent or PS technique. The detailed 29 30 inclusion and exclusion criteria for the present study are listed in Table 2. The planned

31 http://bmjopen.bmj.com/ 32 enrollment duration is between December 2015 and December 2018, and the enrollment 33 34 period may be extended if necessary. There were 446 patients enrolled until September 35 36 2017. 37 38 The randomization serial number for patients will be performed by Interactive Web

39 on October 1, 2021 by guest. Protected copyright. 40 Randomization System (IWRS). The randomization serial number for each participating 41 42 center will be undergone by the same system. 43 44 45 Study intervention and medication 46 47 Patients allocated to the two-stent group will receive double kissing (DK) crush, or culotte 48 49 technique. 50 51 DK crush technique. DK crush stenting technique has been described in details elsewhere 52 53 7,10-12. Briefly, a stent with stent/artery ratio of 1.1:1 is advanced into side branch (SB). 54 55 Another balloon with balloon/artery ratio of 1:1 is positioned in main vessel (MV). Inflating 56 57 5 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 SB stent with 2-3mm protrusion into MV, and then the stent balloon and SB wire are 4 5 removed after confirming that there was no dissection in distal SB by angiogram. Inflating 6 7 previous balloon in MV performs first crush. First kissing balloon inflation is performed 8 9 after rewiring SB from the proximal stent cell. MV stent with stent/artery ratio of 1.1:1 is 10 11 inflated and crushed SB stent again, which then followed by rewiring SB and final kissing 12 13 balloon inflation (FKBI). Proximal optimization technique (POT) is recommended to 14 15 perform before and after FKBI. Post dilatation with non-complaint balloon is recommended 16 For peer review only 17 for all stent, with suggested inflation pressure > 18 atm. 18 13 19 Culotte technique. Culotte stenting has been described in details elsewhere . 20 21 Provisional stenting technique. PS was defined as a stent implantation in the main vessel 22 with the jailed wire or jailed balloon protecting SB 14,15, followed by kissing balloon 23 24 dilatation if there was at least one of following: >type B dissection and TIMI flow < 3 at the 25 26 ostial side branch 5. An additional stent was required for the side branch if any of the 27 28 following issues was observed after kissing balloon inflation: > type B dissection or 29 30 thrombolysis in myocardial infarction (TIMI) flow < 3. POT is also recommended after MV

31 http://bmjopen.bmj.com/ 32 stenting. 33 34 Intracoronary imaging. Intracoronary imaging tools such as intravascular ultrasound 35 36 (IVUS), or optical coherence tomography (OCT) are at the discretion of the operators. 37 38 Study stents. Stents for all implanted lesions are drug-eluting stents (DESs), including

39 on October 1, 2021 by guest. Protected copyright. 40 Firebird-2, or Firehawk (Microport Co., Shanghai, China); EXCEL (Jiwei Co., Shandong, 41 42 China); BuMA stent (Sino Medical, Tianjin, China); Partner or Nano (Lepu Med, Beijing, 43 44 China); Xience or Xience Prime (Abbott Vascular, Santa Clara, California); and Endeavor 45 Resolute or Endeavor Integrity (Medtronic, Minneapolis, Minnesota). 46 47 Medication. All patients in the trial are treated with dual antiplatelet therapy for at least 48 49 one year according to contemporary guidelines and local practice. A loading dose of aspirin 50 51 (300mg) and clopidogrel (300mg, or ticagrelor 180mg) are recommended at least 6 hours 52 53 before PCI procedure. Heparin or an alternative antithrombotic agent (such as bivalirudin) 54 55 must be used during the procedure to maintain the activated clotting time (ACT) >280 56 57 6 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 24 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 seconds. After PCI, lifelong aspirin in a dose of 100mg/d will be prescribed. Duration of 4 5 clopidogrel treatment with 75mg/d (or ticagrelor with 90mg twice a day) is at least 6 7 12-month. 8 9 10 11 Biomarker assessment. Total creatine kinase (CK), CK-Myocardial-Band isoenzyme (MB), 12 13 and troponin T/I are dynamically measured before the procedure and until 72 h 14 15 post-procedure. 16 For peer review only 17 18 19 Study endpoints 20 21 The primary endpoint in the present trial is TLF at 12 months after indexed procedure, 22 defined by the composite of cardiac death, target vessel MI, and TLR. The major secondary 23 24 endpoints include all cause death, MI, target-vessel revascularization (TVR), in-stent 25 26 restenosis, stroke, and each individual component of the primary endpoint. The safety 27 28 endpoint is the risk of Academic Research Consortium (ARC) defined stent thrombosis. 29 30 Other endpoints are listed in Table 3. The detailed definitions of study endpoints are

31 http://bmjopen.bmj.com/ 32 described in the Appendix. 33 34 All endpoints are site-reported in an electronic web-based capture system with 35 36 additional submission of supporting medical documents. All clinical events are assessed by 37 38 an independent committee that was blinded to the study.

39 on October 1, 2021 by guest. Protected copyright. 40 41 42 Follow-up 43 44 After hospital discharge, clinical follow-up is performed with visits (preferred) or telephone 45 contact at 1-, 6-, and 12-month. Follow-up will be continued to 5 year after index procedure 46 47 annually. Angiographic follow-up will be encouraged for all patients, will be undergone at 48 49 13-month after index procedure unless clinically indicated earlier. 50 51 52 53 Angiographic analysis 54 55 56 57 7 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 Quantitative coronary angiographic (QCA) analysis at baseline, post-procedure and 4 5 follow-up is performed by the QCA-laboratories at Nanjing Heart Center. The images are 6 7 analyzed by two experienced technicians who are blinded to the study design, with the 8 9 inter- and intra-observer variability under 5% (Kappa test). 10 11 Basic angiograms for all lesions should consist of at least injections after intracoronary 12 13 injection of 100-200 μg nitroglycerin. Bifurcation-view must be gained for all patients; there 14 15 should be an angulation difference between the two baseline angiograms of at least 30°. The 16 For peer review only 17 diagnostic/guiding catheter should be well visible, near the center of the angiogram and 18 19 filled with dye. The index lesions should be well visible, near the center of the angiogram 20 21 and shown without foreshortening. Between the pre- and post-angiograms all balloon 22 inflations and stent implantations should be documented by short cine-runs. 23 24 25 26 Statistical analysis 27 28 All analysis will be performed in the intent-to-treat (ITT) population, defined as all patients 29 30 randomized, regardless of the treatment actually received. The primary variable is time from

31 http://bmjopen.bmj.com/ 32 randomization to first occurrence of any event from TLF. From previous studies, we 33 34 hypothesized that the rate of a 1-year TLF would be 15% in the systematic two-stent 35 36 technique group and 25% in the provisional stenting group. Accordingly, a total sample size 37 38 of 600 is needed to detect a power of 0.8 (Type error = 0.2, = 0.05, 2-tailed). Because

39 on October 1, 2021 by guest. Protected copyright. 40 of the considerable uncertainty, the enrollment is extended to 660 patients (10% 41 42 increment). 43 44 The distribution of continuous variables will be assessed by the Kolmogrov-Smirnov test. 45 Categorical variables are expressed as frequencies or percentages and compared by 46 47 Chi-square statistics or Fisher's exact test. Continuous variables are summarized as means ± 48 49 standard deviation (SD) or median and compared using Students’ t-test (for normal data) 50 51 and Mann-Whitney U-test (for non-normally distributed variables). Survival curves with 52 53 time-to-event data are generated by the Kaplan-Meier method and compared using the 54 55 log-rank test. Comparison between the two groups will be performed using the Cox 56 57 8 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 24 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 proportional hazard model. A p value <0.05 is considered statistically significance. All 4 5 analyses are performed with the use of the statistical program SPSS 24.0 (SPSS Institute Inc, 6 7 Chicago, Illinois). 8 9 The extensive subgroup analysis will be performed to evaluate variation of treatment 10 11 effects, as well as a test of interaction with treatment for each subgroup variable. The 12 13 substudies of clinical factors include age (age > 75 years old), sex, diabetes mellitus, 14 15 hyperlipidemia, hypertension, current smoking, acute coronary syndrome, cardiac 16 For peer review only 17 dysfunction (left ventricular ejection fraction < 40%), and renal insufficiency (estimated 18 2 19 glomerular filtration rate < 60ml/min/1.73 m ). In addition, the substudies of angiographic 20 21 and procedural factors include unprotected distal left main bifurcation lesion, the use of 22 IVUS, and complete revascularization. Therefore, there are in total of 12 prespecified 23 24 subgroup analyses to explore the consistency of effects on two-stent techniques for complex 25 26 bifurcation lesions. 27 28 29 30 Trial organization

31 http://bmjopen.bmj.com/ 32 The trial has been designed by the principal investigator (PI) and the executive committee. 33 34 The executive committee members are also responsible for reporting the results, and 35 36 drafting the manuscripts. The executive committee, together with the steering committee, 37 38 the data and safety monitoring committee, and the independent endpoints adjudication

39 on October 1, 2021 by guest. Protected copyright. 40 committee are involved in the present trial. 41 42 All centers with experience in two-stent techniques (including DK crush and culotte) can 43 44 participate in the study. The details about trial organization are listed in the Appendix. 45

46 47 Discussion 48 49 Several randomized studies have demonstrated that PS technique using a jailed wire in the 50 51 SB is the gold standard treatment for the majority of bifurcation lesions1-6, however, the 52 53 bifurcation lesions enrolled in these studies were not all true bifurcation lesions, either 54 55 moderate narrow, or focus lesion at the SB ostium. DKCRUSH trial7 has demonstrated 56 57 9 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 that two-stent technique using DK-crush was associated with lower rate of TVR in true 4 5 coronary bifurcation lesions with SB lesion length of 15mm compared with PS. 6 7 Meta-analysis also showed that two-stent technique remained an optional treatment for 8 9 true bifurcation lesions with large side branches16. In addition, consensus from European 10 11 Bifurcation Club17 suggested that true bifurcations with large side branches and ostial 12 13 disease extending more than 5 mm from the carina are likely to require two-stent 14 15 techniques. Therefore, a novel bifurcation classification is needed to identify which 16 For peer review only 17 bifurcation lesions should be treated with two-stent techniques instead of provisional 18 19 stenting. 20 21 The practical and easy-to-use classification was proposed in DEFINITION registry by 22 Shao-Liang Chen9, which including 2 major criteria and 6 minor criteria. According to the 23 24 newly established criteria, 70% exhibited simple bifurcation lesions, and the remaining 30% 25 26 were classified as CBLs in 3660 patients with true coronary bifurcation lesions (Medina 27 28 1,1,1 and 0,1,1) and an SB diameter ≥2.5 mm by visual estimation. As was expected, 29 30 two-stent techniques did not show any benefits over provisional stenting for the simple

31 http://bmjopen.bmj.com/ 32 bifurcation lesions. However, for CBLs two-stent techniques were associated with less 33 34 in-hospital mortality and one-year MACE than PS. The important finding will be further 35 36 verified in the randomized DEFINITION-trial. 37 38 Left main (LM) bifurcation lesions are unique bifurcation lesions. Not only the diameter of

39 on October 1, 2021 by guest. Protected copyright. 40 SB is bigger, but also bifurcation angle is huger compared with non-LM bifurcation. The 41 42 culotte stenting with bare metal stents has been largely abandoned because of high 43 44 restenosis rates. Since the introduction of DESs, culotte stenting has regained its 45 popularity. Murasato reported the restriction of the stent expansion like a “napkin ring” in 46 47 culotte stenting using close-cell design stents18. In our bench study, even using open-cell 48 49 design stents in T type bifurcation, significant stent underexpansion was revealed in culotte 50 51 stenting contrast to DK crush19. DKCRUSH- trial had confirmed that DK crush was 52 53 associated with lower TLR and stent thrombosis for LM bifurcation compared with culotte 54 55 stenting at 3-year follow-up 10,20. Considering the shortages of culotte stenting, we strongly 56 57 10 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 24 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 recommend use of culotte stenting in non-LM bifurcation instead of LM bifurcations. PS with 4 5 jailed balloon is a safer alternative than jailed wire to protect SB, especially for high risk of 6 7 SB occlusion after MV stenting 14,15. Giving CBLs will be enrolled in the study, if a patient is 8 9 randomized into PS group, either jailed balloon or jailed wire will be allowed to use at the 10 11 discretion of the operators. 12 13 14 Conclusions 15 16 Strategies for coronaryFor bifurcationpeer lesions review should be individualized.only PS is the default 17 18 approach for simple bifurcation lesions. The DEFINITION study is investigating whether 19 20 systematic two-stent technique will be superior to PS in CBLs regarding the incidence of TLF 21 22 at 12 months. 23 24 25 26 27 28 29 30

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1 2 3 Table 1. Criteria of complex bifurcation lesions 4 Criteria Lesion characteristics 5 6 Major 1 Distal LM bifurcation: SB-DS ≥70% and SB lesion length ≥10 mm 7 Major 2 Non-LM bifurcation: SB-DS ≥90% and SB lesion length ≥10 mm 8 Minor 1 Moderate to severe calcification 9 Minor 2 Multiple lesions 10 11 Minor 3 Bifurcation angle <45° or >70° 12 Minor 4: Main vessel RVD <2.5 mm 13 Minor 5 Thrombus-containing lesions 14 15 Minor 6 MV lesion length ≥25 mm 16 Major 1 + any 2 minorFor 1–6 peer = complex bifurcation review lesion only 17 Major 2 + any 2 minor 1–6 = complex bifurcation lesion 18 19 20 21 22 23 24 25 26 27 28 29 30

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1 2 3 Table 2 Inclusion and exclusion criteria 4 Inclusion Criteria: 5 6 1. Provision of informed consent prior to any study specific procedures; 7 2. Men and women 18 years and older; 8 3. Established indication to PCI according to the guidelines of American Heart Association 9 and American College of Cardiology; 10 11 4. Native coronary lesion suitable for drug-eluting stent placement; 12 5. True bifurcation lesions (Medina 0,1,1/1,1,1 /1,0,1); 13 6. Reference vessel diameter in side branch ≥2.5mm by visual estimation. 14 Exclusion Criteria: 15 16 1. Pregnancy Forand breast feedingpeer mother; review only 17 2. Co-morbidity with an estimated life expectancy of < 50 % at 12 months; 18 3. Scheduled major surgery in the next 12 months; 19 20 4. Inability to follow the protocol and comply with follow-up requirements or any other 21 reason that the investigator feels would place the patient at increased risk; 22 5. Previous enrolment in this study or treatment with an investigational drug or device 23 under another study protocol in the past 30 days; 24 25 6. Known allergy against ticagrelor, or against clopidogrel, or aspirin History of major 26 hemorrhage (intracranial, gastrointestinal, etc.); 27 7. Chronic total occlusion lesion in either LAD, or LCX or RCA not re-canalized; 28 29 8. Severe calcification needing rotational atherectomy； 30 9. Patient with STEMI (within 24-hour from the onset of chest pain to admission). 31 http://bmjopen.bmj.com/ 32 33 34

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1 2 3 Table 3. Study endpoints. 4 Primary endpoint 5 6 ò Target lesion failure: composite of cardiac death, target vessel myocardial infarction 7 (MI), and target lesion revascularization (TLR) at 12 months 8 Secondary endpoints 9 ò All-cause death: cardiac death, non-cardiac death 10 11 ò MI: periprocedural MI, spontaneous MI 12 ò Revascularization: TLR, target vessel revascularization (TVR) 13 ò Stroke: ischemic stroke, hemorrhagic stroke 14 ò 15 Combined endpoint of all-cause death, MI, TVR 16 ò In-stent restenosisFor peer review only 17 ò Other outcome parameters: NYHA functional class, Braunwald class, net gain of lumen 18 diameter, contrast volume, procedural time, devices consumed during indexed 19 20 procedure, X-ray exposure time, X-ray dose, DAP-total, DAP-record, DAP-fluoro 21 Safety endpoints 22 ò Stent thrombosis 23 ò Bleeding complications 24 25 26

27 28 29 30

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1 2 3 Author affiliations 4 1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 5 6 China; 7 2Department of Cardiology, The General Hospital of Shenyang Military, Shenyang, China; 8 3Department of Cardiology, Nanjing Heart Center, Nanjing, China; 9 4Department of Cardiology, Xijing Hospital, 4th Military Medical University, Xi’an, China; 10 5 11 Medicine Siriraj Hospital, Bangkok, Thailand; 12 6Department of Cardiology, Taicang People’s Hospital, Taicang, China; 13 7Department of Cardiology, Anhui Provincial Hospital, Hefei, China; 14 8Department of Cardiology, Huainan Eastern Hospital, Huainan, China; 15 16 9Department of Cardiology,For peer Yixin People’s review Hospital, Yixin, China;only 17 10Department of Cardiology, Cangzhou Central Hospital, Cangzhou, China; 18 11Binawaluya Cardiac Center, Jakarta, Indonesia; 19 12 20 Guangzhou Red Cross Hospital, Guangzhou, China; 21 13Shanghai Ruijin Hospital, Shanghai, China; 22 14Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 23 Wuhan, China; 24 25 15Medistra Hospital, University of Indonesia, Jakarta, Indonesia; 26 16Department of Cardiology, Gansu Provincial Hospital, Lanzhou, China; 27 17Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 28 29 China; 30 18Department of Cardiology, Changshu First People’s Hospital, Changshu, China;

31 19Cheng-Hsin General Hospital, Taipei, China; http://bmjopen.bmj.com/ 32 20Zhangjiagang First People’s Hospital, ZhangjiaGang, China; 33 21 34 Changzhou Hospital of Traditional Chinese Medicine, Changzhou, China; 35 22Jiangxi Provincial People’s Hospital, Nanchang, China; 36 23Bangkok General Hospital, Bangkok, Thailand; 37 24Xia’Men Zhongshan Hospital, Xia’Men, China; 38 25 39 Huainan First People’s Hospital, Huainan, China; on October 1, 2021 by guest. Protected copyright. 40 26Jintan People’s Hospital, Jintan, China; 41 27Wuxi Third People 's Hospital, Wuxi, China; 42 28 43 Daqing Oil General Hospital, Daqing, China; 44 29The Second Hospital of Shandong University, Ji’nan, China; 45 30Xinyang Central Hospital, Xinyang, China; 46 31Fujian Union Hospital, Fuzhou, China; 47 32 48 Jilin Heart Hospital, Changchun, China; 49 33Otamendi Hospital, Buenos Aires, Argentina; 50 34Chuzhou First People 's Hospital, Chuzhou, China; 51 35 52 Huainan Xinhua Hospital, Huainan, China; 53 36Bangplee Hospital, Bangkok, Thailand; 54 37Huai’an Second People’s Hospital, Huai’an, China; 55 38Qingdao Fuwai Hospital, Qingdao, China; 56 57 15 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 39The Affiliated Hospital of Guangdong Medical University, Guangdong, China; 4 40University of Turin, Turin, Italy; 5 41 6 The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; 7 42Xuyi People’s Hospital, Xuyi, China; 8 43Wuxi Huishan District People’s Hospital, Wuxi, China; 9 44Anqing First People’s Hospital, Anqing, China; 10 45 11 Liyang Hospital of Traditional Chinese Medicine, Liyang, China; 12 46Lianyungang Hospital of Traditional Chinese Medicine, Lianyungang, China; 13 14 Acknowledgements The authors appreciate the contributions of Ling Lin, Hai-Mei Xu, and 15 16 Ying-Ying Zhao toFor data collection. peer They reviewalso acknowledge onlyBao-Xiang Duan, Lin Lin, Ji Yong, 17 and Linda Lison for their contribution in the data and safety monitoring. 18 19 20 Contributiors 21 SLC made substantial contributions to study conception and design, and to the drafting and 22 critical revision of the manuscript. JJZ and XFG wrote the first draft. YLH, JK, LT, and ZG 23 provided data management and statistical expertise. DT, SL, LKM, FL, SY, JZ, MM, LL, RYZ, 24 25 HSZ, TS, PX, ZNJ, LH, WHY, XSQ, QHL, LH, CP, YW, LJL, LZ, XMW, SYW, QHL, JQY, LLC, FL, AER, 26 LMZ, SQD, KV, YSZ, MYY, CC, IS, YX, YLT, ZLS, QJ, YHZ, XW, FY, NLT, SL, and ZZL provided 27 comments and suggestions in critical revision of the article. All authors approved the final 28 29 version of the article. 30

31 Funding The present trial was support by National Science Foundation of China (NSFC http://bmjopen.bmj.com/ 32 81270191, NSFC 91439118) and Health and Family Planning Commission Foundation of 33 34 Nanjing (YKK16124) 35 36 Competing interests None declared. 37

39 Patient consent Obtained. on October 1, 2021 by guest. Protected copyright. 40 41 Ethics approval Institutional Review Board at each participating center. 42 43 44 Provenance and peer review Not commissioned; externally peer reviewed. 45 46 Open Access This is an Open Access article distributed in accordance with the 47 48 Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits 49 others to distribute, remix, adapt, build upon this work non-commercially, and license their 50 derivative works on different terms, provided the original work is properly cited and the use 51 52 is non-commercial. See: http://creativecommons. org/licenses/by-nc/4.0/ 53 54 55 56 57 16 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 24 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 Figure legend 4 5 Figure. 1 Flowchart of study design. 6 7 SB: side branch; RVD: reference vessel diameter; DS: diameter stenosis; LMd: left main distal 8 9 bifurcation; MV: main vessel; PS: provisional stenting; TLF: target lesion failure; TV-MI: 10 11 target-vessel myocardial infarction; TLR: target lesion revascularization. 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30

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1 2 3 Reference 4 1. Colombo A, Bramucci E, Sacca S, et al. Randomized study of the crush technique 5 6 versus provisional side-branch stenting in true coronary bifurcations: the CACTUS 7 (Coronary Bifurcations: Application of the Crushing Technique Using 8 Sirolimus-Eluting Stents) Study. Circulation 2009;119(1):71-78. 9 2. Ferenc M, Gick M, Kienzle RP, et al. Randomized trial on routine vs. provisional 10 11 T-stenting in the treatment of de novo coronary bifurcation lesions. Eur Heart J 12 2008;29(23):2859-2867. 13 3. Hildick-Smith D, de Belder AJ, Cooter N, et al. Randomized trial of simple versus 14 complex drug-eluting stenting for bifurcation lesions: the British Bifurcation 15 16 Coronary For Study: peer old, new, review and evolving only strategies. Circulation 17 2010;121(10):1235-1243. 18 4. Pan M, de Lezo JS, Medina A, et al. Rapamycin-eluting stents for the treatment of 19 20 bifurcated coronary lesions: a randomized comparison of a simple versus complex 21 strategy. Am Heart J 2004;148(5):857-864. 22 5. Steigen TK, Maeng M, Wiseth R, et al. Randomized study on simple versus complex 23 stenting of coronary artery bifurcation lesions: the Nordic bifurcation study. 24 25 Circulation 2006;114(18):1955-1961. 26 6. Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate 27 sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 28 29 2004;109(10):1244-1249. 30 7. Chen SL, Santoso T, Zhang JJ, et al. A randomized clinical study comparing double

31 kissing crush with provisional stenting for treatment of coronary bifurcation lesions: http://bmjopen.bmj.com/ 32 results from the DKCRUSH-II (Double Kissing Crush versus Provisional Stenting 33 34 Technique for Treatment of Coronary Bifurcation Lesions) trial. J Am Coll Cardiol 35 2011;57(8):914-920. 36 8. Lin QF, Luo YK, Lin CG, Peng YF, Zhen XC, Chen LL. Choice of stenting strategy in true 37 coronary artery bifurcation lesions. Coron Artery Dis 2010;21(6):345-351. 38

39 9. Chen SL, Sheiban I, Xu B, et al. Impact of the complexity of bifurcation lesions treated on October 1, 2021 by guest. Protected copyright. 40 with drug-eluting stents: the DEFINITION study (Definitions and impact of complEx 41 biFurcation lesIons on clinical outcomes after percutaNeous coronary IntervenTIOn 42 43 using drug-eluting steNts). JACC Cardiovasc Interv 2014;7(11):1266-1276. 44 10. Chen SL, Xu B, Han YL, et al. Comparison of double kissing crush versus Culotte 45 stenting for unprotected distal left main bifurcation lesions: results from a 46 multicenter, randomized, prospective DKCRUSH-III study. J Am Coll Cardiol 47 48 2013;61(14):1482-1488. 49 11. Chen SL, Ye F, Zhang JJ, et al. [DK crush technique: modified treatment of bifurcation 50 lesions in coronary artery]. Chin Med J (Engl) 2005;118(20):1746-1750. 51 52 12. Chen SL, Zhang JJ, Ye F, et al. Study comparing the double kissing (DK) crush with 53 classical crush for the treatment of coronary bifurcation lesions: the DKCRUSH-1 54 Bifurcation Study with drug-eluting stents. Eur J Clin Invest 2008;38(6):361-371. 55 13. Chevalier B, Glatt B, Royer T, Guyon P. Placement of coronary stents in bifurcation 56 57 18 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 24 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 lesions by the "culotte" technique. Am J Cardiol 1998;82(8):943-949. 4 14. Depta JP, Patel Y, Patel JS, et al. Long-term clinical outcomes with the use of a 5 6 modified provisional jailed-balloon stenting technique for the treatment of nonleft 7 main coronary bifurcation lesions. Catheter Cardiovasc Interv 2013;82(5):E637-646. 8 15. Singh J, Patel Y, Depta JP, et al. A modified provisional stenting approach to coronary 9 bifurcation lesions: clinical application of the "jailed-balloon technique". J Interv 10 11 Cardiol 2012;25(3):289-296. 12 16. Gao XF, Zhang YJ, Tian NL, et al. Stenting strategy for coronary artery bifurcation with 13 drug-eluting stents: a meta-analysis of nine randomised trials and systematic review. 14 EuroIntervention 2014;10(5):561-569. 15 16 17. Stankovic ForG, Lefevre peer T, Chieffo A, reviewet al. Consensus from only the 7th European Bifurcation 17 Club meeting. EuroIntervention 2013;9(1):36-45. 18 18. Murasato Y, Hikichi Y, Horiuchi M. Examination of stent deformation and gap 19 20 formation after complex stenting of left main coronary artery bifurcations using 21 microfocus computed tomography. J Interv Cardiol 2009;22(2):135-144. 22 19. Rab T, Sheiban I, Louvard Y, Sawaya FJ, Zhang JJ, Chen SL. Current Interventions for 23 the Left Main Bifurcation. JACC Cardiovasc Interv 2017;10(9):849-865. 24 25 20. Chen SL, Xu B, Han YL, et al. Clinical Outcome After DK Crush Versus Culotte Stenting 26 of Distal Left Main Bifurcation Lesions: The 3-Year Follow-Up Results of the 27 DKCRUSH-III Study. JACC Cardiovasc Interv 2015;8(10):1335-1342. 28 29 30

31 http://bmjopen.bmj.com/ 32 33 34 35 36 37 38

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Flowchart of study design.

31 http://bmjopen.bmj.com/ 32 49x35mm (300 x 300 DPI) 33 34 35 36 37 38

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1 2 3 Appendix 1. Definitions of major study endpoints 4 Endpoint Definition 5 Death ò Cardiovascular death includes sudden cardiac death, 6 7 death due to acute myocardial infarction (MI), 8 arrhythmia, heart failure, stroke, other cardiovascular 9 causes, or bleeding 10 ò Non-cardiovascular death is defined as any death 11 12 with known cause not of cardiac or vascular cause 13 ò All deaths are considered cardiac in origin unless a 14 non-cardiac cause is confirmed clinically or at autopsy. 15 Myocardial Post-procedure MI: occurrence within 48 hours after PCI 16 For peer review only 17 infarction ò Patients with normal baseline CK-MB: the peak CK-MB 18 measured within 48 hours of the procedure rises to ≥ 19 10 × upper reference limit (URL), or to ≥ 5 × URL with 20 new pathologic Q-waves in at least 2 contiguous leads 21 or new persistent left bundle branch block (LBBB) 22 23 ò Patients with elevated baseline CK-MB in whom the 24 biomarker levels are stable or falling: the CK-MB rises 25 by an absolute increment equal to those levels 26 recommended above from the most recent 27 28 pre-procedure level 29 Spontaneous MI: occurrence more than 48 hours after PCI 30 ò The rise of cardiac biomarkers (CK-MB or troponin) > 31 1x URL, with one of the follows: http://bmjopen.bmj.com/ 32 ‹ Evidence of prolonged ischemia as demonstrated by 33 34 prolonged chest pain 35 ‹ Ischemic ST-segment changes or new pathological Q 36 waves 37 38 ‹ Angiographic evidence of a flow limiting complication

39 ‹ Imaging evidence of new loos of viable myocardium or on October 1, 2021 by guest. Protected copyright. 40 new regional wall motion abnormality 41 42 Target vessel MI: spontaneous MI associated with target 43 vessel, which was identified by electrocardiographic 44 changes or coronary angiography. 45 Each MI will also be classified as ST-segment elevation MI 46 (STEMI) and non-ST-segment elevation MI (NSTEMI) 47 48 Revascularization Target lesion revascularization (TLR) 49 ò Repeat revascularization (including PCI and coronary 50 artery bypass grafting) for target lesions, in the presence 51 of symptoms or objective signs of ischemia 52 53 Target vessel revascularization (TVR) 54 ò Repeat revascularization (including PCI and coronary 55 artery bypass grafting) for target vessels, in the presence 56 of symptoms or objective signs of ischemia 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 Target vessel non-target lesion revascularization 4 ò Target vessel non-target lesion consists of a lesion in the 5 epicardial vessel/branch/graft that contains the target 6 7 lesion; however, this lesion is outside of the target lesion 8 by at least 5 mm distal or proximal to the target lesion 9 determined by quantitative coronary angiography 10 Stent thrombosis Academic Research Consortium (ARC) classification 11 12 Definite stent thrombosis 13 ò Symptoms suggestive of an acute coronary syndrome and 14 angiographic or pathological confirmation of stent 15 thrombosis 16 For peerProbable stent review thrombosis only 17 18 ò Unexplained death within 30 days or target vessel 19 myocardial infarction without angiographic confirmation 20 of stent thrombosis 21 Possible stent thrombosis 22 23 ò Any unexplained death after 30 days 24 Stent thrombosis will also be classified as acute stent 25 thrombosis (0œ24 hours after PCI), subacute stent thrombosis 26 (24 hours-30 days), late stent thrombosis (31 daysœ1 year), or 27 very late stent thrombosis (>1 year) 28 29 Bleeding Bleeding Academic Research Consortium (BARC) 30 classification 31 Type 0: no bleeding http://bmjopen.bmj.com/ 32 Type 1: bleeding that is not actionable and doses not cause 33 34 the patient to seek unscheduled performance of studies, 35 hospitalization, or treatment 36 Type 2: any overt, actionable sign of hemorrhage that 37 doses not fit the criteria for 3, 4, or 5 38 Type 3: 39 on October 1, 2021 by guest. Protected copyright. 40 ò Type 3a: overt bleeding with hemoglobin drop of 3 to 41 5 g/dl; any transfusion with overt bleeding 42 ò Type 3b: overt bleeding with hemoglobin drop ≥ 43 5g/dl; cardiac tamponade; bleeding requiring surgical 44 45 intervention for control; bleeding requiring 46 intravenous vasoactive agents 47 ò Type 3c: intracranial hemorrhage; intraocular 48 bleeding compromising vision 49 50 Type 4: CABG-related bleeding 51 Type 5: fatal bleeding 52 Stroke Global or focal cerebral, spinal cord, or retinal injury 53 resulting in acute neurological dysfunction and was further 54 classified into ischemic and hemorrhagic stroke 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 24 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 Appendix 2. Trial organization 4 Principal investigator: 5 Shao-Liang Chen, Nanjing First Hospital, Nanjing Medical University 6 7 8 Steering committee: 9 Shao-Liang Chen, Gregg W Stone, Bo Xu , Imad Sheiban, Ya-ling Han 10 11 12 Core laboratory: 13 Nanjing Heart Center 14 15 Study statistician: 16 School of PublicFor Health, peer Nanjing Medical review University only 17 18 19 Data and safety monitoring committee: 20 Bao-Xiang Duan, Lin Lin, Ji Yong, Linda Lison 21 22 23 Participating hospitals and collaborators of DEFINITION ⅡⅡⅡ trial: 24 25 1. Nanjing First Hospital, Nanjing Medical University, Nanjing, China; 26 2. The General Hospital of Shenyang Military, Shenyang, China; 27 3. Xijing Hospital, 4th Military Medical University, Xi’an, China; 28 29 4. Medicine Siriraj Hospital, Bangkok, Thailand; 30 5. Taicang People’s Hospital, Taicang, China;

31 6. Anhui Provincial Hospital, Hefei, China; http://bmjopen.bmj.com/ 32 7. Huainan Eastern Hospital, Huainan, China; 33 34 8. Yixin People’s Hospital, Yixin, China; 35 9. Cangzhou Central Hospital, Cangzhou, China; 36 10. Binawaluya Cardiac Center, Jakarta, Indonesia; 37 11. Guangzhou Red Cross Hospital, Guangzhou, China; 38 12. Shanghai Ruijin Hospital, Shanghai, China; 39 on October 1, 2021 by guest. Protected copyright. 40 13. Tongji Hospital, Tongji Medical College, Huazhong University of Science and 41 Technology, Wuhan, China; 42 14. Medistra Hospital, University of Indonesia, Jakarta, Indonesia; 43 15. Gansu Provincial Hospital, Lanzhou, China; 44 45 16. Beijing Anzhen Hospital, Capital Medical University, Beijing, China; 46 17. Changshu First People’s Hospital, Changshu, China; 47 18. Cheng-Hsin General Hospital, Taipei, China; 48 19. Zhangjiagang First People’s Hospital, ZhangjiaGang, China; 49 20. Changzhou Hospital of Traditional Chinese Medicine, Changzhou, China; 50 51 21. Jiangxi Provincial People’s Hospital, Nanchang, China; 52 22. Bangkok General Hospital, Bangkok, Thailand; 53 23. Xia’Men Zhongshan Hospital, Xia’Men, China; 54 24. Huainan First People’s Hospital, Huainan, China; 55 56 25. Jintan People’s Hospital, Jintan, China; 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 24 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 26. Wuxi Third People 's Hospital, Wuxi, China; 4 27. Daqing Oil General Hospital, Daqing, China; 5 28. The Second Hospital of Shandong University, Ji’nan, China; 6 7 29. Xinyang Central Hospital, Xinyang, China; 8 30. Fujian Union Hospital, Fuzhou, China; 9 31. Jilin Heart Hospital, Changchun, China; 10 32. Otamendi Hospital, Buenos Aires, Argentina; 11 12 33. Chuzhou First People 's Hospital, Chuzhou, China; 13 34. Huainan Xinhua Hospital, Huainan, China; 14 35. Bangle Hospital, Bangkok, Thailand; 15 36. Huai’an Second People’s Hospital, Huai’an, China; 16 37. QingdaoFor Fuwai Hospital, peer Qingdao, review China; only 17 18 38. The Affiliated Hospital of Guangdong Medical University, Guangdong, China; 19 39. University of Turin, Turin, Italy; 20 40. The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; 21 41. Xuyi People’s Hospital, Xuyi, China; 22 23 42. Wuxi Huishan District People’s Hospital, Wuxi, China; 24 43. Anqing First People’s Hospital, Anqing, China; 25 44. Liyang Hospital of Traditional Chinese Medicine, Liyang, China; 26 45. Lianyungang Hospital of Traditional Chinese Medicine, Lianyungang, China; 27 28 29 30

31 http://bmjopen.bmj.com/ 32 33 34 35 36 37 38

39 on October 1, 2021 by guest. Protected copyright. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

The treatment effects of systematic two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: Rationale and design of a prospective, randomized, and multicenter DEFINITION ⅡⅡⅡ Trial

For peer review only Journal: BMJ Open

Manuscript ID bmjopen-2017-020019.R1

Article Type: Protocol

Date Submitted by the Author: 24-Nov-2017

Tresukosol, Damras; Medicine Siriraj Hospital, Mahidol University, http://bmjopen.bmj.com/ cardiology Lu, Shu; Taicang People‘s Hospital, Department of Cardiology Ma, Likun; Anhui Provincial Hospital, Department of Cardiology Li, Feng; Huainan Eastern Hospital, Department of Cardiology Yang, Song; Yixin People‘s Hospital, Department of Cardiology Zhang, Jun; Cangzhou Central Hospital, Department of Cardiology Munawar, Muhammad; Binawaluya Cardiac Center, Department of Cardiology

Li, Li; Guangzhou Red Cross Hospital, Department of Cardiology on October 1, 2021 by guest. Protected copyright. Zhang, Ruiyan; Shanghai Ruijin Hospital, Department of Cardiology Zeng, Hesong; Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Department of Cardiology Santoso, Teguh; Medistra Hospital, University of Indonesia, cardiology Xie, Ping; Gansu Provincial Hospital, Department of Cardiology Jin, Zening; Beijing Anzhen Hospital, Department of Cardiology Han, Leng; Changshu First People‘s Hospital, Department of Cardiology Yin, Wei-Hsian; Cheng-Hsin General Hospital, cardiology Qian, Xuesong; Zhangjiagang First People‘s Hospital, Department of Cardiology Li, Qihua; Changzhou Hospital of Traditional Chinese Medicine, Department of Cardiology Hong, Lang; Jiangxi Provincial People's Hospital, Department of Cardiology Paiboon, Chotnoparatpat; Bangkok General Hospital, cardiology Wang, Yan; Xia‘Men Zhongshan Hospital, cardiology Liu, Lijun; Huainan First People‘s Hospital, Department of Cardiology Zhou, Lei; Jintan People‘s Hospital, cardiology Wu, Xueming; Wuxi Third People 's Hospital, cardiology Wen, Shangyu; Daqing Oil General Hospital, cardiology

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1 2 3 4 Lu, Qinghua; The Second Hospital of Shandong University, cardiology Yuan, Junqiang; Xinyang Central Hospital, cardiology 5 Chen, Lianglong; Fujian Union Hospital, cardiology 6 Lavarra, Francesco; Jilin Heart Hospital, cardiology 7 Rodríguez, Alfredo E. ; Otamendi Hospital, cardiology 8 Zhou, Limin; Chuzhou First People 's Hospital, cardiology 9 Ding, Shiqin; Huainan Xinhua Hospital, cardiology 10 Vichairuangthum, Kitigon; Bangplee Hospital, cardiology Zhu, Yuansheng; Huai‘an Second People‘s Hospital, cardiology 11 Yu, Mengyue; Qingdao Fuwai Hospital, cardiology 12 Chen, Chan; The Affiliated Hospital of Guangdong Medical University, 13 cardiology 14 Sheiban, Imad; Pederzoli Hospital, cardiology 15 Xia, Yong; The Affiliated Hospital of Xuzhou Medical University, cardiology 16 Tian, Yulong; Xuyi People‘s Hospital, cardiology For peerShang, Zhenglu review ; Wuxi Huishan District only People‘s Hospital, cardiology 17 Jiang, Qing; Anqing First People‘s Hospital, cardiology 18 Zhen, Yonghong; Liyang Hospital of Traditional Chinese Medicine, 19 cardiology 20 Wang, Xin; Lianyungang Hospital of Traditional Chinese Medicine, 21 cardiology 22 Ye, Fei; Nanjing First Hospital, Department of Cardiology Tian, Nailiang; Nanjing First Hospital, Department of Cardiology 23 Lin, Song; Nanjing First Hospital, Department of Cardiology 24 Liu, Zhizhong; Nanjing First Hospital, Department of Cardiology 25 Chen, Shao-Liang; Nanjing First Hospital, Nanjing Medical University, 26 Department of Cardiology 27 Primary Subject 28 Cardiovascular medicine Heading: 29 30 Secondary Subject Heading: Medical management

31 http://bmjopen.bmj.com/ coronary bifurcation lesions, systematic two-stent techniques, provisional 32 Keywords: stenting technique 33 34 35 36 37 38

39 on October 1, 2021 by guest. Protected copyright. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 36 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 The treatment effects of systematic two-stent and provisional stenting techniques in 4 5 2 patients with complex coronary bifurcation lesions: Rationale and design of a 6 7 3 prospective, randomized, and multicenter DEFINITION Trial 8 ⅡⅡⅡ 9 10 4 11 1 1 2 3 4 1 12 5 Jun-Jie Zhang, Xiao-Fei Gao, Ya-Ling Han, Jing Kan, Ling Tao, Zhen Ge, Damras

13 5 6 7 8 9 10 11 14 6 Tresukosol, Shu Lu, Li-Kun Ma, Feng Li, Song Yang, Jun Zhang, Muhammad Munawar, 15 7 Li Li,12 Rui-Yan Zhang,13 He-Song Zeng,14 Teguh Santoso,15 Ping Xie,16 Ze-Ning Jin,17 Leng 16 For peer review only 17 8 Han,18 Wei-Hsian Yin,19 Xue-Song Qian,20 Qi-Hua Li,21 Lang Hong,22 Chotnoparatpat 18 19 9 Paiboon,23 Yan Wang,24 Li-Jun Liu,25 Lei Zhou,26 Xue-Ming Wu,27 Shang-Yu Wen,28 Qing-Hua 20 21 10 Lu,29 Jun-Qiang Yuan,30 Liang-Long Chen,31 Francesco Lavarra,32 Alfredo E. Rodríguez,33 22 23 11 Li-Min Zhou,34 Shi-Qin Ding,35 Kitigon Vichairuangthum,36 Yuan-Sheng Zhu,37 Meng-Yue Yu,38 24 25 12 Chan Chen,39 Imad Sheiban,40 Yong Xia,41 Yu-Long Tian,42 Zheng-Lu Shang,43 Qing Jiang,44 26 27 13 Yong-Hong Zhen,45 Xin Wang,46 Fei Ye,1 Nai-Liang Tian,1 Song Lin,1 Zhi-Zhong Liu,1 28 29 14 Shao-Liang Chen,1,3* 30

31 15 http://bmjopen.bmj.com/ 32 33 16 Zhang JJ and Gao XF contributed equally to this work. 34 35 17 36 37 18 *Correspondence author: Shao-Liang Chen, Department of cardiology, Nanjing First 38 19 Hospital, Nanjing Medical University; No. 68 Changle road, 210006 Nanjing, China; Tel & Fax: 39 on October 1, 2021 by guest. Protected copyright. 40 20 +86-25-52208048; E-mail: [email protected]. 41 42 21 43 22 44 45 46 47 48 49 50 51 52 53 54 55 56 57 1 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 36 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 Abstract 4 5 2 Introduction: Provisional stenting (PS) for simple coronary bifurcation lesions is the 6 7 3 mainstay of treatment. A systematic two-stent approach is widely used for complex 8 9 4 bifurcation lesions (CBLs). However, a randomized comparison of PS and two-stent 10 11 5 techniques for CBLs has never been studied. Accordingly, the present study is designed to 12 13 6 elucidate the benefits of two-stent treatment over PS in patients with CBLs. 14 15 7 Methods and analysis: This DEFINITION Ⅱ study is a prospective, multinational, 16 For peer review only 17 8 randomized, endpoint-driven trial to compare the benefits of the two-stent technique with 18 19 9 PS for CBLs. A total of 660 patients with CBLs will be randomized in a 1:1 fashion to receive 20 21 10 either PS or the two-stent technique. The primary endpoint is the rate of 12-month target 22 23 11 lesion failure (TLF) defined as the composite of cardiac death, target vessel myocardial 24 25 12 infarction (MI), and clinically driven target lesion revascularization (TLR). The major 26 27 13 secondary endpoints include all causes of death, MI, target vessel revascularization (TVR), 28 29 14 in-stent restenosis, stroke, and each individual component of the primary endpoints. The 30

31 15 safety endpoint is the occurrence of definite or probable stent thrombosis (ST). http://bmjopen.bmj.com/ 32 33 16 Ethics and dissemination: The study protocol and informed consent have been approved 34 35 17 by the Institutional Review Board of Nanjing First Hospital, and accepted by each 36 37 18 participating center. Written informed consent was obtained from all enrolled patients. 38 19 Findings of the study will be published in a peer-reviewed journal and disseminated at 39 on October 1, 2021 by guest. Protected copyright. 40 20 conferences. 41 42 21 Trial registration number: NCT02284750; Pre-results. 43 44 22 45 23 46 47 48 49 50 51 52 53 54 55 56 57 2 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 36 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 Strengths and limitations of this study 4 2 ‹ This is the first prospective, multinational, randomized, endpoint-driven trial to 5 6 3 compare the systematic two-stent and provisional stenting (PS) techniques in patients 7 4 with complex coronary bifurcation lesions (CBLs). 8 5 9 6 ‹ This study is built on the DEFINITION registry, which for the first time introduced an 10 11 7 anatomical differentiation of coronary bifurcation lesion complexity and reported that 12 8 PS for CBLs was associated with an increment of cardiac death compared with simple 13 9 bifurcation lesions. 14 10 15 16 11 ‹ Selection of primaryFor and peer secondary review endpoints is in accordance only with current practice in 17 12 other cardiovascular clinical trials. 18 13 19 20 14 ‹ All participating sites are well-versed in two-stent techniques (including double kissing 21 15 crush and culotte), which may not be reflective of clinical practice in smaller hospitals. 22 16 23 17 24 25 18 26 19 27 28 29 30

31 http://bmjopen.bmj.com/ 32 33 34 35 36 37 38

39 on October 1, 2021 by guest. Protected copyright. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 3 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 36 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 Background 4 5 2 Percutaneous coronary intervention (PCI) for bifurcation lesions is technically demanding 6 7 3 and has a poor outcome at follow-up, as reflected by more frequent occurrences of in-stent 8 4 restenosis (most localize at the ostium of the daughter branch) and more requirements for 9 10 5 revascularization. For a great majority of coronary bifurcation lesions, particularly when a 11 12 6 small (diameter<2.0 mm) side branch (SB) with a focal (usually <5 mm in length) lesion is 13 14 7 involved, provisional stenting (PS) is considered as the default approach1-6. However, the 15 16 8 efficacy of PS for aFor larger (≥2.5 peer mm in diameter) review SB with a longeronly lesion (>5 mm in length) is 17 18 9 underreported7,8. Furthermore, there is a lack of angiographical criteria for differentiating 19 20 10 simple from complex bifurcation lesions (CBLs). In this regard, the DEFINITION registry 21 22 11 study 9 introduced for the first time an anatomical differentiation of bifurcation lesion 23 24 12 complexity, which consisted of 2 major and 6 minor criteria. Based on the DEFINITION 25 26 13 criteria, a CBLs is defined as one major plus any two minor criteria. Investigators further 27 28 14 reported that PS for CBLs was associated with an increment in cardiac death and major 29 15 adverse cardiac events (MACE) compared with simple bifurcation lesions. Unfortunately, PS 30 31 16 has not been compared with systematic two-stent techniques in a randomized fashion for http://bmjopen.bmj.com/ 32 33 17 patients with CBLs. Therefore, we design this prospective, multi-center, randomized 34 35 18 (DEFINITION ) study to investigate the superiority of systematic two-stent approaches 36 37 19 for PS treatment for patients with CBLs, as classified by the DEFINITION registry. 38

39 20 on October 1, 2021 by guest. Protected copyright. 40 41 21 Methods and analysis 42 43 22 Study hypothesis 44 45 23 This study is designed to test the hypothesis that the application of systematic two-stent 46 47 24 techniques will lead to a lower rate of target lesion failure (TLF), including cardiac death, 48 49 25 target-vessel myocardial infarction (MI), or clinically driven target lesion revascularization 50 51 26 (TLR), compared to the PS technique, in patients with CBLs at 12 months after the indexed 52 27 PCI procedure. CBLs are defined according to the DEFINITION study 9, and the criteria are 53 54 28 shown in Table 1. 55 56 57 4 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 36 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 4 5 2 Study design 6 7 3 This is a prospective, multi-center, randomized, controlled, superiority trial at up to 45 sites 8 9 4 worldwide (Appendix) to enroll 660 subjects with CBLs in a native coronary artery. The 10 11 5 overall study flowchart is presented in Figure 1. This study has been registered at 12 13 6 clinicaltrials.gov (NCT02284750), according to the statement of the International 14 15 7 Committee of Medical Journal Editors. 16 For peer review only 17 8 18 19 9 Study population and randomization 20 21 10 The 660 patients scheduled for elective PCI with CBLs suitable for drug-eluting stent (DES) 22 11 implantation are openly randomized 1:1 to either the systematic two-stent or the PS 23 24 12 technique. Detailed inclusion and exclusion criteria for the present study are listed in Table 25 26 13 2. The planned enrollment duration is between December 2015 and December 2018, and 27 28 14 the enrollment period may be extended if necessary. There are 446 patients enrolled up to 29 30 15 September 2017.

31 http://bmjopen.bmj.com/ 32 16 A randomization serial number for patients will be created by the Interactive Web 33 34 17 Randomization System (IWRS). The randomization serial number for each participating 35 36 18 center will be generated by the same system. 37 38 19

39 on October 1, 2021 by guest. Protected copyright. 40 20 Study intervention and medication 41 42 21 Patients allocated to the two-stent group will receive the double kissing (DK) crush, or the 43 44 22 culotte technique. 45 23 DK crush technique. The DK crush stenting technique has been described in detail 46 47 24 elsewhere 7,10-12. Briefly, a stent with a stent/artery ratio of 1.1:1 is advanced into a side 48 49 25 branch (SB). Another balloon with balloon/artery ratio of 1:1 is positioned in the main 50 51 26 vessel (MV). Inflating the SB stent with a 2-3 mm protrusion into the MV, and then the stent 52 53 27 balloon and SB wire are removed after confirming that there is no dissection in the distal SB 54 55 28 by angiogram. Inflating the previous balloon in the MV performs the first crush. First, the 56 57 5 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 36 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 kissing balloon inflation is performed after rewiring the SB from the proximal stent cell. An 4 5 2 MV stent with a stent/artery ratio of 1.1:1 is inflated and crushes the SB stent again, which is 6 7 3 then followed by rewiring the SB and the final kissing balloon inflation (FKBI). A proximal 8 9 4 optimization technique (POT) should be performed before and after FKBI. Post dilatation 10 11 5 with a non-complaint balloon is recommended for all stents, with a suggested inflation 12 13 6 pressure > 18 atm. 14 15 7 Culotte technique. Culotte stenting has been described in detail elsewhere13. In brief, the 16 For peer review only 17 8 MV and SB are both wired. The SB is then stented first with a wire jailed in the MV. The MV is 18 19 9 rewired through the stent struts (through a distal stent strut where possible), following 20 21 10 balloon dilation and MV stenting. Then, second, rewiring the SB from a distal access is 22 11 undertaken. A mandatory attempted FKBI is performed. Post-dilations with non-complaint 23 24 12 balloon are undertaken to optimize stent expansion. POT in the stented segment proximal to 25 26 13 the bifurcation is recommended. 27 28 14 Provisional stenting technique. PS is defined as a stent implantation in the MV with the 29 30 15 jailed wire or jailed balloon protecting the SB 14,15, followed by kissing balloon dilatation if

31 http://bmjopen.bmj.com/ 32 16 there is at least one of the following: > type B dissection and thrombolysis in myocardial 33 34 17 infarction (TIMI) flow < 3 at the ostial SB5. An additional stent is required for the SB if any of 35 36 18 the following issues are observed after kissing balloon inflation: > type B dissection or TIMI 37 38 19 flow < 3. POT is also recommended after MV stenting.

39 on October 1, 2021 by guest. Protected copyright. 40 20 Intracoronary imaging. Intracoronary imaging tools, such as intravascular ultrasound 41 42 21 (IVUS) or optical coherence tomography (OCT), are at the discretion of the operators. 43 44 22 Study stents. Stents for all implanted lesions are drug-eluting stents (DESs), including 45 23 Firebird-2, or Firehawk (Microport Co., Shanghai, China); EXCEL (Jiwei Co., Shandong, 46 47 24 China); BuMA stent (Sino Medical, Tianjin, China); Partner or Nano (Lepu Med, Beijing, 48 49 25 China); Xience or Xience Prime (Abbott Vascular, Santa Clara, California); and Endeavor 50 51 26 Resolute or Endeavor Integrity (Medtronic, Minneapolis, Minnesota). 52 53 27 Medication. All patients in the trial are treated with dual antiplatelet therapy for at least 54 55 28 one year, according to contemporary guidelines and local practice. A loading dose of aspirin 56 57 6 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 36 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 (300 mg) and clopidogrel (300 mg), or ticagrelor 180 mg) is recommended at least 6 hours 4 5 2 before the PCI procedure. Heparin or an alternative antithrombotic agent (such as 6 7 3 bivalirudin) must be used during the procedure to maintain an activated clotting time 8 9 4 (ACT) >280 seconds. After the PCI, a lifelong dosage of aspirin at 100 mg/d will be 10 11 5 prescribed. The duration of clopidogrel treatment with 75 mg/d (or ticagrelor with 90 mg 12 13 6 twice a day) is at least 12 months. 14 15 7 16 For peer review only 17 8 Biomarker assessment. Total creatine kinase (CK), CK-myocardial-band isoenzyme (MB), 18 19 9 and troponin T/I are dynamically measured before the procedure and until 72 h 20 21 10 post-procedure. 22 11 23 24 12 Study endpoints 25 26 13 The primary endpoint in the present trial is TLF at 12 months after the indexed procedure, 27 28 14 as defined by the composite of cardiac death, target vessel MI, and clinically driven TLR. The 29 30 15 major secondary endpoints include all causes of death, MI, target-vessel revascularization

31 http://bmjopen.bmj.com/ 32 16 (TVR), in-stent restenosis, stroke, and each individual component of the primary endpoints. 33 34 17 The safety endpoint is the risk of Academic Research Consortium (ARC)-defined stent 35 36 18 thrombosis. Other endpoints are listed in Table 3. Detailed definitions of the study endpoints 37 38 19 are described in the supplemental material.

39 on October 1, 2021 by guest. Protected copyright. 40 20 All endpoints are site-reported in an electronic web-based capture system with the 41 42 21 additional submission of supporting medical documents. All clinical events are assessed by 43 44 22 an independent committee that was blinded to the study. 45 23 46 47 24 Follow-up 48 49 25 After hospital discharge, clinical follow-up is performed with visits (preferred) or telephone 50 51 26 contact at 1-, 6-, and 12-month. Follow-up will be continued annually until 5 years after the 52 53 27 index procedure. An angiographic follow-up will be encouraged for all patients, and it will be 54 55 56 57 7 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 36 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 conducted 13 months after the index procedure, unless clinically indicated earlier. An 4 5 2 independent committee that is blinded to the study assesses all clinical events. 6 7 3 8 9 4 Angiographic analysis 10 11 5 Quantitative coronary angiographic (QCA) analysis at baseline, post-procedure and 12 13 6 follow-up is performed by the QCA-laboratories at the Nanjing Heart Center. The images are 14 15 7 analyzed by two experienced technicians who are blinded to the study design, with an inter- 16 For peer review only 17 8 and intra-observer variability under 5% (Kappa test). 18 19 9 Basic angiograms for all lesions should consist of at least injections after intracoronary 20 21 10 injection of 100-200 μg of nitroglycerin. A bifurcation-view must be gained for all patients; 22 11 there should be an angulation difference between the two baseline angiograms of at least 23 24 12 30°. The diagnostic/guiding catheter should be well visible, near the center of the 25 26 13 angiogram and filled with dye. The index lesions should be well visible, near the center of 27 28 14 the angiogram and shown without foreshortening. Between the pre- and post-angiograms, 29 30 15 all balloon inflations and stent implantations should be documented by short cine-runs.

31 http://bmjopen.bmj.com/ 32 16 33 34 17 Statistical analysis 35 36 18 All analyses will be performed on the intent-to-treat (ITT) population, defined as all patients 37 38 19 randomized, regardless of the treatment actually received. The primary variable is time from

39 on October 1, 2021 by guest. Protected copyright. 40 20 randomization to first occurrence of any event from the TLF. From previous studies, we 41 42 21 hypothesized that the rate of a 1-year TLF would be 15% in the systematic two-stent 43 44 22 technique group and 25% in the provisional stenting group. Accordingly, a total sample size 45 23 of 600 is needed to detect a power of 0.8 (Type error = 0.2, = 0.05, 2-tailed). Because 46 47 24 of the considerable uncertainty, the enrollment is extended to 660 patients (10% 48 49 25 increment). 50 51 26 The distribution of continuous variables will be assessed by the Kolmogrov-Smirnov test. 52 53 27 Categorical variables are expressed as frequencies or percentages and compared by 54 55 28 Chi-square statistics or Fisher's exact test. Continuous variables are summarized as the 56 57 8 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 36 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 means ± standard deviation (SD) or median and compared using Students’ t-test (for normal 4 5 2 data) and Mann-Whitney U test (for non-normally distributed variables). Survival curves 6 7 3 with time-to-event data are generated by the Kaplan-Meier method and compared using the 8 9 4 log-rank test. Comparisons between the two groups will be performed using the Cox 10 11 5 proportional hazard model. A p value <0.05 is considered statistically significant. All 12 13 6 analyses are performed with the use of the statistical program SPSS 24.0 (SPSS Institute Inc, 14 15 7 Chicago, Illinois). 16 For peer review only 17 8 The extensive subgroup analysis will be performed to evaluate variation of treatment 18 19 9 effects, as well as a test of interaction with the treatment for each subgroup variable. The 20 21 10 sub studies of clinical factors include age (age > 75 years old), sex, diabetes mellitus, 22 11 hyperlipidemia, hypertension, current smoking, acute coronary syndrome, cardiac 23 24 12 dysfunction (left ventricular ejection fraction < 40%), and renal insufficiency (estimated 25 26 13 glomerular filtration rate < 60 ml/min/1.73 m2). In addition, the sub studies of angiographic 27 28 14 and procedural factors include an unprotected distal left main bifurcation lesion, the use of 29 30 15 IVUS, and complete revascularization. Therefore, there are a total of 12 prespecified

31 http://bmjopen.bmj.com/ 32 16 subgroup analyses to explore the consistency of effects on two-stent techniques for complex 33 34 17 bifurcation lesions. 35 36 18 37 38 19 Ethics and dissemination

39 on October 1, 2021 by guest. Protected copyright. 40 20 The study is performed in accordance with the Declaration of Helsinki and International 41 42 21 Conference on Harmonization of Good Clinical Practices. The study protocol and informed 43 44 22 consent have been reviewed and approved by the Institutional Review Board of Nanjing 45 23 First Hospital (KY20141128-01-KS-01, in the supplemental material), and accepted by each 46 47 24 participating center. Written informed consent for participation in the trial was obtained 48 49 25 from all enrolled patients. Dissemination of the results will include conference presentations 50 51 26 and publications in peer-reviewed journals. 52 53 27 54 55 28 Trial organization 56 57 9 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 36 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 The trial was designed by the principal investigator (PI) and the executive committee. The 4 5 2 executive committee members are also responsible for reporting the results, and drafting 6 7 3 the manuscripts. The executive committee, together with the steering committee, the data 8 9 4 and safety monitoring committee, and the independent endpoints adjudication committee 10 11 5 are involved in the present trial. 12 13 6 All centers with experience in two-stent techniques (including DK crush and culotte) can 14 15 7 participate in the study. Details about trial organization are listed in the supplemental 16 For peer review only 17 8 material. 18 19 9 20 21 10 Discussion 22 11 Several randomized studies have demonstrated that the PS technique using a jailed wire in 23 24 12 the SB is the gold standard treatment for the majority of bifurcation lesions1-6; however, the 25 26 13 bifurcation lesions enrolled in these studies were not all true bifurcation lesions. They were 27 28 14 either moderate narrow or focused lesions at the SB ostium. The DKCRUSH trial7 29 30 15 demonstrated that the two-stent technique using a DK crush was associated with a lower

31 http://bmjopen.bmj.com/ 32 16 rate of TVR in true coronary bifurcation lesions with an SB lesion length of 15 mm, 33 34 17 compared with PS. A meta-analysis also showed that the two-stent technique remained an 35 36 18 optional treatment for true bifurcation lesions with a large SB16. In addition, the consensus 37 38 19 of the European Bifurcation Club17 was that true bifurcations with a large SB and ostial

39 on October 1, 2021 by guest. Protected copyright. 40 20 disease extending more than 5 mm from the carina are likely to require two-stent 41 42 21 techniques. Therefore, a novel bifurcation classification is needed to identify which 43 44 22 bifurcation lesions should be treated with two-stent techniques instead of PS. 45 23 A practical and easy-to-use classification was proposed in the DEFINITION registry by 46 47 24 Shao-Liang Chen9, which included 2 major criteria and 6 minor criteria. According to the 48 49 25 newly established criteria, 70% exhibited simple bifurcation lesions, and the remaining 30% 50 51 26 were classified as CBLs in 3660 patients with true coronary bifurcation lesions (Medina 52 53 27 1,1,1 and 0,1,1) and an SB diameter ≥2.5 mm by visual estimation. As was expected, the 54 55 28 two-stent technique did not show any benefits over PS for the simple bifurcation lesions. 56 57 10 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 36 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 However, for CBLs, two-stent techniques were associated with less in-hospital mortality and 4 5 2 one-year MACE than PS. This important finding will be further verified in the randomized 6 7 3 DEFINITION-trial. 8 9 4 Left main (LM) bifurcation lesions are unique bifurcation lesions. The diameter of the SB is 10 11 5 bigger, and the bifurcation angle is also larger compared with that of a non-LM bifurcation. 12 13 6 Culotte stenting with bare metal stents has been largely abandoned because of high 14 15 7 restenosis rates. Since the introduction of DESs, culotte stenting has regained its 16 For peer review only 17 8 popularity. Murasato reported restriction of the stent expansion such as a “napkin ring” in 18 18 19 9 culotte stenting, using close-cell design stents . In our bench study, even using open-cell 20 21 10 design stents in T type bifurcations, significant stent under expansion was revealed in 22 11 culotte stenting, in contrast to DK crush19. The DKCRUSH- trial confirmed that DK crush 23 24 12 was associated with a lower TLR and stent thrombosis for LM bifurcation, compared with 25 26 13 culotte stenting at 3-year follow-up 10,20. Considering the shortages of culotte stenting, we 27 28 14 strongly recommend the use of culotte stenting in non-LM bifurcation instead of LM 29 30 15 bifurcations. PS with a jailed balloon is a safer alternative than a jailed wire to protect the SB,

31 http://bmjopen.bmj.com/ 32 16 especially for a high risk of SB occlusion after MV stenting 14,15. Given that CBLs will be 33 34 17 enrolled in the study if a patient is randomized into the PS group, either the use of a jailed 35 36 18 balloon or a jailed wire will be allowed at the discretion of the operators. 37 19 38

39 20 Conclusions on October 1, 2021 by guest. Protected copyright. 40 41 21 Strategies for coronary bifurcation lesions should be individualized. PS is the default 42 43 22 approach for simple bifurcation lesions. The DEFINITION study is investigating whether 44 45 23 systematic two-stent technique will be superior to PS in CBLs, regarding the incidence of 46 47 24 TLF at 12 months. 48 49 25 50 26 51 52 53 54 55 56 57 11 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 36 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 Table 1. Criteria of complex bifurcation lesions 4 Criteria Lesion characteristics 5 6 Major 1 Distal LM bifurcation: SB-DS ≥70% and SB lesion length ≥10 mm 7 Major 2 Non-LM bifurcation: SB-DS ≥90% and SB lesion length ≥10 mm 8 Minor 1 Moderate to severe calcification 9 Minor 2 Multiple lesions 10 11 Minor 3 Bifurcation angle <45° or >70° 12 Minor 4: Main vessel RVD <2.5 mm 13 Minor 5 Thrombus-containing lesions 14 15 Minor 6 MV lesion length ≥25 mm 16 Major 1 + any 2 minorFor 1–6 peer = complex bifurcation review lesion only 17 Major 2 + any 2 minor 1–6 = complex bifurcation lesion 18 19 2 20 3 21 22 23 24 25 26 27 28 29 30

31 http://bmjopen.bmj.com/ 32 33 34 35 36 37 38

39 on October 1, 2021 by guest. Protected copyright. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 12 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 36 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 Table 2 Inclusion and exclusion criteria 4 Inclusion Criteria: 5 6 1. Provision of informed consent prior to any study specific procedures; 7 2. Men and women 18 years and older; 8 3. Established indication for PCI according to the guidelines of American Heart Association 9 and American College of Cardiology; 10 11 4. Native coronary lesion suitable for drug-eluting stent placement; 12 5. True bifurcation lesions (Medina 0,1,1/1,1,1 /1,0,1); 13 6. Reference vessel diameter in side branch ≥2.5 mm by visual estimation. 14 Exclusion Criteria: 15 16 1. Pregnancy Foror breast-feeding peer mother; review only 17 2. Co-morbidity with an estimated life expectancy of < 50% at 12 months; 18 3. Scheduled major surgery in the next 12 months; 19 20 4. Inability to follow the protocol and comply with follow-up requirements or any other 21 reason that the investigator feels would place the patient at increased risk; 22 5. Previous enrolment in this study or treatment with an investigational drug or device 23 under another study protocol in the past 30 days; 24 25 6. Known allergy to ticagrelor clopidogrel, or aspirin, history of major hemorrhage 26 (intracranial, gastrointestinal, etc.); 27 7. Chronic total occlusion lesion in either LAD, or LCX or RCA not re-canalized; 28 29 8. Severe calcification needing rotational atherectomy； 30 9. Patient with STEMI (within 24-hour from the onset of chest pain to admission). 31 2 http://bmjopen.bmj.com/ 32 33 3 34 4 35 36 37 38

39 on October 1, 2021 by guest. Protected copyright. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 13 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 36 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 Table 3. Study endpoints. 4 Primary endpoint 5 6 ò Target lesion failure: composite of cardiac death, target vessel myocardial infarction 7 (MI), and target lesion revascularization (TLR) at 12 months 8 Secondary endpoints 9 ò All-cause death: cardiac death, non-cardiac death 10 11 ò MI: periprocedural MI, spontaneous MI 12 ò Revascularization: TLR, target vessel revascularization (TVR) 13 ò Stroke: ischemic stroke, hemorrhagic stroke 14 ò 15 Combined endpoint of all-cause death, MI, TVR 16 ò In-stent restenosisFor peer review only 17 ò Other outcome parameters: NYHA functional class, Braunwald class, net gain of lumen 18 diameter, contrast volume, procedural time, devices consumed during indexed 19 20 procedure, X-ray exposure time, X-ray dose, DAP-total, DAP-record, DAP-fluoro 21 Safety endpoints 22 ò Stent thrombosis 23 ò Bleeding complications 24 25 2 26 3 27 28 4 29 30

31 http://bmjopen.bmj.com/ 32 33 34 35 36 37 38

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1 2 3 1 Author affiliations 4 2 1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 5 6 3 China; 7 4 2Department of Cardiology, The General Hospital of Shenyang Military, Shenyang, China; 8 5 3Department of Cardiology, Nanjing Heart Center, Nanjing, China; 9 6 4Department of Cardiology, Xijing Hospital, 4th Military Medical University, Xi’an, China; 10 5 11 7 Medicine Siriraj Hospital, Bangkok, Thailand; 12 8 6Department of Cardiology, Taicang People’s Hospital, Taicang, China; 13 9 7Department of Cardiology, Anhui Provincial Hospital, Hefei, China; 14 10 8Department of Cardiology, Huainan Eastern Hospital, Huainan, China; 15 16 11 9Department of Cardiology,For peer Yixin People’s review Hospital, Yixin, China;only 17 12 10Department of Cardiology, Cangzhou Central Hospital, Cangzhou, China; 18 13 11Binawaluya Cardiac Center, Jakarta, Indonesia; 19 12 20 14 Guangzhou Red Cross Hospital, Guangzhou, China; 21 15 13Shanghai Ruijin Hospital, Shanghai, China; 22 16 14Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 23 17 Wuhan, China; 24 25 18 15Medistra Hospital, University of Indonesia, Jakarta, Indonesia; 26 19 16Department of Cardiology, Gansu Provincial Hospital, Lanzhou, China; 27 20 17Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 28 29 21 China; 30 22 18Department of Cardiology, Changshu First People’s Hospital, Changshu, China;

31 23 19Cheng-Hsin General Hospital, Taipei, China; http://bmjopen.bmj.com/ 32 24 20Zhangjiagang First People’s Hospital, ZhangjiaGang, China; 33 21 34 25 Changzhou Hospital of Traditional Chinese Medicine, Changzhou, China; 35 26 22Jiangxi Provincial People’s Hospital, Nanchang, China; 36 27 23Bangkok General Hospital, Bangkok, Thailand; 37 28 24Xia’Men Zhongshan Hospital, Xia’Men, China; 38 25 39 29 Huainan First People’s Hospital, Huainan, China; on October 1, 2021 by guest. Protected copyright. 40 30 26Jintan People’s Hospital, Jintan, China; 41 31 27Wuxi Third People 's Hospital, Wuxi, China; 42 28 43 32 Daqing Oil General Hospital, Daqing, China; 44 33 29The Second Hospital of Shandong University, Ji’nan, China; 45 34 30Xinyang Central Hospital, Xinyang, China; 46 35 31Fujian Union Hospital, Fuzhou, China; 47 32 48 36 Jilin Heart Hospital, Changchun, China; 49 37 33Otamendi Hospital, Buenos Aires, Argentina; 50 38 34Chuzhou First People 's Hospital, Chuzhou, China; 51 35 52 39 Huainan Xinhua Hospital, Huainan, China; 53 40 36Bangplee Hospital, Bangkok, Thailand; 54 41 37Huai’an Second People’s Hospital, Huai’an, China; 55 42 38Qingdao Fuwai Hospital, Qingdao, China; 56 57 15 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 36 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 39The Affiliated Hospital of Guangdong Medical University, Guangdong, China; 4 2 40University of Turin, Turin, Italy; 5 41 6 3 The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; 7 4 42Xuyi People’s Hospital, Xuyi, China; 8 5 43Wuxi Huishan District People’s Hospital, Wuxi, China; 9 6 44Anqing First People’s Hospital, Anqing, China; 10 45 11 7 Liyang Hospital of Traditional Chinese Medicine, Liyang, China; 12 8 46Lianyungang Hospital of Traditional Chinese Medicine, Lianyungang, China; 13 9 14 10 Acknowledgements The authors appreciate the contributions of Ling Lin, Hai-Mei Xu, and 15 16 11 Ying-Ying Zhao toFor data collection. peer They reviewalso acknowledge onlyBao-Xiang Duan, Lin Lin, Ji Yong, 17 12 and Linda Lison for their contribution in the data and safety monitoring. 18 13 19 20 14 Contributiors 21 15 SLC made substantial contributions to study conception and design, and to the drafting and 22 16 critical revision of the manuscript. JJZ and XFG wrote the first draft. YLH, JK, LT, and ZG 23 17 provided data management and statistical expertise. DT, SL, LKM, FL, SY, JZ, MM, LL, RYZ, 24 25 18 HSZ, TS, PX, ZNJ, LH, WHY, XSQ, QHL, LH, CP, YW, LJL, LZ, XMW, SYW, QHL, JQY, LLC, FL, AER, 26 19 LMZ, SQD, KV, YSZ, MYY, CC, IS, YX, YLT, ZLS, QJ, YHZ, XW, FY, NLT, SL, and ZZL provided 27 20 comments and suggestions in critical revision of the article. All authors approved the final 28 29 21 version of the article. 30 22

31 23 Funding The present trial was support by National Science Foundation of China (NSFC http://bmjopen.bmj.com/ 32 24 81270191, NSFC 91439118) and Health and Family Planning Commission Foundation of 33 34 25 Nanjing (YKK16124) 35 26 36 27 Competing interests None declared. 37 28 38

39 29 Patient consent Obtained. on October 1, 2021 by guest. Protected copyright. 40 30 41 31 Ethics approval The study protocol and informed consent have been reviewed and 42 43 32 approved by the Institutional Review Board of Nanjing First Hospital 44 33 (KY20141128-01-KS-01), and accepted by each participating center. Version of this protocol 45 34 was 1.2, and was approved on March 9, 2016 (in the supplemental material). 46 35 47 48 36 Provenance and peer review Not commissioned; externally peer reviewed. 49 37 50 38 Open Access This is an Open Access article distributed in accordance with the 51 52 39 Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits 53 40 others to distribute, remix, adapt, build upon this work non-commercially, and license their 54 41 derivative works on different terms, provided the original work is properly cited and the use 55 42 is non-commercial. See: http://creativecommons. org/licenses/by-nc/4.0/ 56 57 16 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 36 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 Figure legend 4 5 2 Figure 1 Flowchart of study design. 6 3 SB: side branch; RVD: reference vessel diameter; DS: diameter stenosis; LMd: left main distal 7 8 4 bifurcation; MV: main vessel; PS: provisional stenting; TLF: target lesion failure; TV-MI: 9 10 5 target-vessel myocardial infarction; TLR: target lesion revascularization. 11 12 6 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30

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1 2 3 1 Reference 4 2 1. Colombo A, Bramucci E, Sacca S, et al. Randomized study of the crush technique 5 6 3 versus provisional side-branch stenting in true coronary bifurcations: the CACTUS 7 4 (Coronary Bifurcations: Application of the Crushing Technique Using 8 5 Sirolimus-Eluting Stents) Study. Circulation 2009;119(1):71-78. 9 6 2. Ferenc M, Gick M, Kienzle RP, et al. Randomized trial on routine vs. provisional 10 11 7 T-stenting in the treatment of de novo coronary bifurcation lesions. Eur Heart J 12 8 2008;29(23):2859-2867. 13 9 3. Hildick-Smith D, de Belder AJ, Cooter N, et al. Randomized trial of simple versus 14 10 complex drug-eluting stenting for bifurcation lesions: the British Bifurcation 15 16 11 Coronary For Study: peer old, new, review and evolving only strategies. Circulation 17 12 2010;121(10):1235-1243. 18 13 4. Pan M, de Lezo JS, Medina A, et al. Rapamycin-eluting stents for the treatment of 19 20 14 bifurcated coronary lesions: a randomized comparison of a simple versus complex 21 15 strategy. Am Heart J 2004;148(5):857-864. 22 16 5. Steigen TK, Maeng M, Wiseth R, et al. Randomized study on simple versus complex 23 17 stenting of coronary artery bifurcation lesions: the Nordic bifurcation study. 24 25 18 Circulation 2006;114(18):1955-1961. 26 19 6. Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate 27 20 sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 28 29 21 2004;109(10):1244-1249. 30 22 7. Chen SL, Santoso T, Zhang JJ, et al. A randomized clinical study comparing double

31 23 kissing crush with provisional stenting for treatment of coronary bifurcation lesions: http://bmjopen.bmj.com/ 32 24 results from the DKCRUSH-II (Double Kissing Crush versus Provisional Stenting 33 34 25 Technique for Treatment of Coronary Bifurcation Lesions) trial. J Am Coll Cardiol 35 26 2011;57(8):914-920. 36 27 8. Lin QF, Luo YK, Lin CG, Peng YF, Zhen XC, Chen LL. Choice of stenting strategy in true 37 28 coronary artery bifurcation lesions. Coron Artery Dis 2010;21(6):345-351. 38

39 29 9. Chen SL, Sheiban I, Xu B, et al. Impact of the complexity of bifurcation lesions treated on October 1, 2021 by guest. Protected copyright. 40 30 with drug-eluting stents: the DEFINITION study (Definitions and impact of complEx 41 31 biFurcation lesIons on clinical outcomes after percutaNeous coronary IntervenTIOn 42 43 32 using drug-eluting steNts). JACC Cardiovasc Interv 2014;7(11):1266-1276. 44 33 10. Chen SL, Xu B, Han YL, et al. Comparison of double kissing crush versus Culotte 45 34 stenting for unprotected distal left main bifurcation lesions: results from a 46 35 multicenter, randomized, prospective DKCRUSH-III study. J Am Coll Cardiol 47 48 36 2013;61(14):1482-1488. 49 37 11. Chen SL, Ye F, Zhang JJ, et al. [DK crush technique: modified treatment of bifurcation 50 38 lesions in coronary artery]. Chin Med J (Engl) 2005;118(20):1746-1750. 51 52 39 12. Chen SL, Zhang JJ, Ye F, et al. Study comparing the double kissing (DK) crush with 53 40 classical crush for the treatment of coronary bifurcation lesions: the DKCRUSH-1 54 41 Bifurcation Study with drug-eluting stents. Eur J Clin Invest 2008;38(6):361-371. 55 42 13. Chevalier B, Glatt B, Royer T, Guyon P. Placement of coronary stents in bifurcation 56 57 18 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 36 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from

1 2 3 1 lesions by the "culotte" technique. Am J Cardiol 1998;82(8):943-949. 4 2 14. Depta JP, Patel Y, Patel JS, et al. Long-term clinical outcomes with the use of a 5 6 3 modified provisional jailed-balloon stenting technique for the treatment of nonleft 7 4 main coronary bifurcation lesions. Catheter Cardiovasc Interv 2013;82(5):E637-646. 8 5 15. Singh J, Patel Y, Depta JP, et al. A modified provisional stenting approach to coronary 9 6 bifurcation lesions: clinical application of the "jailed-balloon technique". J Interv 10 11 7 Cardiol 2012;25(3):289-296. 12 8 16. Gao XF, Zhang YJ, Tian NL, et al. Stenting strategy for coronary artery bifurcation with 13 9 drug-eluting stents: a meta-analysis of nine randomised trials and systematic review. 14 10 EuroIntervention 2014;10(5):561-569. 15 16 11 17. Stankovic ForG, Lefevre peer T, Chieffo A, reviewet al. Consensus from only the 7th European Bifurcation 17 12 Club meeting. EuroIntervention 2013;9(1):36-45. 18 13 18. Murasato Y, Hikichi Y, Horiuchi M. Examination of stent deformation and gap 19 20 14 formation after complex stenting of left main coronary artery bifurcations using 21 15 microfocus computed tomography. J Interv Cardiol 2009;22(2):135-144. 22 16 19. Rab T, Sheiban I, Louvard Y, Sawaya FJ, Zhang JJ, Chen SL. Current Interventions for 23 17 the Left Main Bifurcation. JACC Cardiovasc Interv 2017;10(9):849-865. 24 25 18 20. Chen SL, Xu B, Han YL, et al. Clinical Outcome After DK Crush Versus Culotte Stenting 26 19 of Distal Left Main Bifurcation Lesions: The 3-Year Follow-Up Results of the 27 20 DKCRUSH-III Study. JACC Cardiovasc Interv 2015;8(10):1335-1342. 28 29 21 30

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30

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39 on October 1, 2021 by guest. Protected copyright. 40 41 42 43 44 45 Flowchart of study design.

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1 Supplemental material 2 3 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 4 5 6 The treatment effects of systematic two-stent and provisional stenting techniques 7 8 9 in patients with complex coronary bifurcation lesions: Rationale and design of a 10 11 12 prospective, randomized, and multicenter DEFINITION Ⅱ Trial 13 14 15 1 1 2 3 4 1 5 6 16 Jun-Jie Zhang, Xiao-Fei Gao, Ya-Ling Han, Jing Kan, Ling Tao, Zhen Ge, Damras Tresukosol, Shu Lu, 17 7 8 9 10 11 12 13 18 Li-Kun Ma, Feng Li, Song Yang,For Jun Zhang, peer Muhammad Munawar,review only Li Li, Rui-Yan Zhang, He-Song 19 14 15 16 17 18 19 20 20 Zeng, Teguh Santoso, Ping Xie, Ze-Ning Jin, Leng Han, Wei-Hsian Yin, Xue-Song Qian, Qi-Hua 21 21 22 23 24 25 26 27 22 Li, Lang Hong, Chotnoparatpat Paiboon, Yan Wang, Li-Jun Liu, Lei Zhou, Xue-Ming Wu, 23 Shang-Yu Wen,28 Qing-Hua Lu,29 Jun-Qiang Yuan,30 Liang-Long Chen,31 Francesco Lavarra,32 Alfredo E. 24 25 Rodríguez,33 Li-Min Zhou,34 Shi-Qin Ding,35 Kitigon Vichairuangthum,36 Yuan-Sheng Zhu,37 Meng-Yue 26 27 Yu,38 Chan Chen,39 Imad Sheiban,40 Yong Xia,41 Yu-Long Tian,42 Zheng-Lu Shang,43 Qing Jiang,44 Yong-Hong 28 29 Zhen,45 Xin Wang,46 Fei Ye,1 Nai-Liang Tian,1 Song Lin,1 Zhi-Zhong Liu,1 Shao-Liang Chen,1,3* 30 31 32 33 Zhang JJ and Gao XF contributed equally to this work. 34

35 http://bmjopen.bmj.com/ 36 37 *Correspondence author: Shao-Liang Chen, Department of cardiology, Nanjing First Hospital, Nanjing 38 39 Medical University; No. 68 Changle road, 210006 Nanjing, China; Tel & Fax: +86-25-52208048; E-mail: 40 41 [email protected]. 42

43 on October 1, 2021 by guest. Protected copyright. 44 45 1 46 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; 47 2 48 Department of Cardiology, The General Hospital of Shenyang Military, Shenyang, China; 49 3Department of Cardiology, Nanjing Heart Center, Nanjing, China; 50 51 4Department of Cardiology, Xijing Hospital, 4th Military Medical University, Xi’an, China; 52 53 5Medicine Siriraj Hospital, Bangkok, Thailand; 54 55 6Department of Cardiology, Taicang People’s Hospital, Taicang, China; 56 57 7Department of Cardiology, Anhui Provincial Hospital, Hefei, China; 58 59 8Department of Cardiology, Huainan Eastern Hospital, Huainan, China; 60 9Department of Cardiology, Yixin People’s Hospital, Yixin, China; 1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 36 BMJ Open

10 1 Department of Cardiology, Cangzhou Central Hospital, Cangzhou, China; 2 11 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 3 Binawaluya Cardiac Center, Jakarta, Indonesia; 4 12 5 Guangzhou Red Cross Hospital, Guangzhou, China; 6 13 7 Shanghai Ruijin Hospital, Shanghai, China; 8 14 9 Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 10 15Medistra Hospital, University of Indonesia, Jakarta, Indonesia; 11 12 16Department of Cardiology, Gansu Provincial Hospital, Lanzhou, China; 13 14 17Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China; 15 16 18Department of Cardiology, Changshu First People’s Hospital, Changshu, China; 17 18 19Cheng-Hsin General Hospital, Taipei, China;For peer review only 19 20 20Zhangjiagang First People’s Hospital, ZhangjiaGang, China; 21 22 21Changzhou Hospital of Traditional Chinese Medicine, Changzhou, China; 23 24 22Jiangxi Provincial People’s Hospital, Nanchang, China; 25 26 23Bangkok General Hospital, Bangkok, Thailand; 27 28 24Xia’Men Zhongshan Hospital, Xia’Men, China; 29 30 25Huainan First People’s Hospital, Huainan, China; 31 32 26Jintan People’s Hospital, Jintan, China; 33 34 27Wuxi Third People 's Hospital, Wuxi, China;

35 http://bmjopen.bmj.com/ 36 28Daqing Oil General Hospital, Daqing, China; 37 38 29The Second Hospital of Shandong University, Ji’nan, China; 39 30 40 Xinyang Central Hospital, Xinyang, China; 41 31 42 Fujian Union Hospital, Fuzhou, China;

43 on October 1, 2021 by guest. Protected copyright. 32 44 Jilin Heart Hospital, Changchun, China; 45 33 46 Otamendi Hospital, Buenos Aires, Argentina; 47 34 48 Chuzhou First People 's Hospital, Chuzhou, China; 49 35Huainan Xinhua Hospital, Huainan, China; 50 51 36Bangplee Hospital, Bangkok, Thailand; 52 53 37Huai’an Second People’s Hospital, Huai’an, China; 54 55 38Qingdao Fuwai Hospital, Qingdao, China; 56 57 39The Affiliated Hospital of Guangdong Medical University, Guangdong, China; 58 59 40University of Turin, Turin, Italy; 60 41The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; 2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 36

42 1 Xuyi People’s Hospital, Xuyi, China; 2 43 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 3 Wuxi Huishan District People’s Hospital, Wuxi, China; 4 44 5 Anqing First People’s Hospital, Anqing, China; 6 45 7 Liyang Hospital of Traditional Chinese Medicine, Liyang, China; 8 46 9 Lianyungang Hospital of Traditional Chinese Medicine, Lianyungang, China; 10 11 12 13 14 15 16 17 18 ForAppendix peer review only Page number 19 20 Appendix 1. Definitions of major study endpoints 4-5 21 22 Appendix 2. Trial organization 6-7 23 24 Appendix 3. Institutional Review Boards 8-11 25 26 Appendix 4. SPIRIT 2013 Checklist 12-16 27 28 29 30 31 32 33 34

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Appendix 1. Definitions of major study endpoints 1 2 Endpoint Definition 3 Death l Cardiovascular death includes sudden cardiac death, death due to acute BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 4 myocardial infarction (MI), arrhythmia, heart failure, stroke, other 5 6 cardiovascular causes, or bleeding 7 l Non-cardiovascular death is defined as any death with known cause not of 8 cardiac or vascular cause 9 10 l All deaths are considered cardiac in origin unless a non-cardiac cause is confirmed 11 clinically or at autopsy. 12 Myocardial Post-procedure MI: occurrence within 48 hours after PCI 13 14 infarction l Patients with normal baseline CK-MB: the peak CK-MB measured within 48 15 hours of the procedure rises to ≥ 10 × upper reference limit (URL), or to ≥ 5 × 16 URL with new pathologic Q-waves in at least 2 contiguous leads or new 17 persistent left bundle branch block (LBBB) 18 For peer review only 19 l Patients with elevated baseline CK-MB in whom the biomarker levels are 20 stable or falling: the CK-MB rises by an absolute increment equal to those 21 levels recommended above from the most recent pre-procedure level 22 23 Spontaneous MI: occurrence more than 48 hours after PCI 24 l The rise of cardiac biomarkers (CK-MB or troponin) > 1x URL, with one of the 25 follows: 26 27 Ø Evidence of prolonged ischemia as demonstrated by prolonged chest pain 28 Ø Ischemic ST-segment changes or new pathological Q waves 29 Ø Angiographic evidence of a flow limiting complication 30 31 Ø Imaging evidence of new loos of viable myocardium or new regional wall 32 motion abnormality 33 34 Target vessel MI: spontaneous MI associated with target vessel (including main

35 vessel [MV] and side branch [SB]), which was identified by electrocardiographic http://bmjopen.bmj.com/ 36 changes or coronary angiography. 37 38 Each MI will also be classified as ST-segment elevation MI (STEMI) and 39 non-ST-segment elevation MI (NSTEMI) 40 Revascularization Target lesion revascularization (TLR) 41 42 l Repeat revascularization (including PCI and coronary artery bypass grafting) for

43 target lesions (including MV and SB), in the presence of symptoms or objective on October 1, 2021 by guest. Protected copyright. 44 signs of ischemia 45 Target vessel revascularization (TVR) 46 47 l Repeat revascularization (including PCI and coronary artery bypass grafting) for 48 target vessels (including MV and SB), in the presence of symptoms or objective 49 signs of ischemia 50 51 Target vessel non-target lesion revascularization 52 l Target vessel non-target lesion consists of a lesion in the epicardial 53 vessel/branch/graft that contains the target lesion; however, this lesion is outside of 54 55 the target lesion by at least 5 mm distal or proximal to the target lesion determined 56 by quantitative coronary angiography 57 Stent thrombosis Academic Research Consortium (ARC) classification 58 Definite stent thrombosis 59 60 l Symptoms suggestive of an acute coronary syndrome and angiographic or pathological confirmation of stent thrombosis 4 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 36

Probable stent thrombosis 1 2 l Unexplained death within 30 days or target vessel myocardial infarction without 3 angiographic confirmation of stent thrombosis BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 4 Possible stent thrombosis 5 6 l Any unexplained death after 30 days 7 Stent thrombosis will also be classified as acute stent thrombosis (0–24 hours after PCI), 8 subacute stent thrombosis (24 hours-30 days), late stent thrombosis (31 days–1 year), or 9 10 very late stent thrombosis (>1 year) 11 Bleeding Bleeding Academic Research Consortium (BARC) classification 12 Type 0: no bleeding 13 Type 1: bleeding that is not actionable and doses not cause the patient to seek 14 15 unscheduled performance of studies, hospitalization, or treatment 16 Type 2: any overt, actionable sign of hemorrhage that doses not fit the criteria for 17 3, 4, or 5 18 For peer review only 19 Type 3: 20 l Type 3a: overt bleeding with hemoglobin drop of 3 to 5 g/dl; any transfusion 21 with overt bleeding 22 23 l Type 3b: overt bleeding with hemoglobin drop ≥ 5g/dl; cardiac tamponade; 24 bleeding requiring surgical intervention for control; bleeding requiring 25 intravenous vasoactive agents 26 l Type 3c: intracranial hemorrhage; intraocular bleeding compromising vision 27 28 Type 4: CABG-related bleeding 29 Type 5: fatal bleeding 30 Stroke Global or focal cerebral, spinal cord, or retinal injury resulting in acute neurological 31 32 dysfunction and was further classified into ischemic and hemorrhagic stroke 33 34

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Appendix 2. Trial organization 1 2 Principal investigator: 3 Shao-Liang Chen, Nanjing First Hospital, Nanjing Medical University BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 4 5 6 Steering committee: 7 Shao-Liang Chen, Gregg W Stone, Bo Xu , Imad Sheiban, Ya-ling Han 8 9 10 Core laboratory: 11 Nanjing Heart Center 12 13 Study statistician: 14 15 School of Public Health, Nanjing Medical University 16 17 Data and safety monitoring committee: 18 For peer review only 19 Bao-Xiang Duan, Lin Lin, Ji Yong, Linda Lison 20 21 22 Participating hospitals and collaborators of DEFINITION Ⅱ trial: 23 24 1. Nanjing First Hospital, Nanjing Medical University, Nanjing, China; 25 2. The General Hospital of Shenyang Military, Shenyang, China; 26 3. Xijing Hospital, 4th Military Medical University, Xi’an, China; 27 28 4. Medicine Siriraj Hospital, Bangkok, Thailand; 29 5. Taicang People’s Hospital, Taicang, China; 30 6. Anhui Provincial Hospital, Hefei, China; 31 32 7. Huainan Eastern Hospital, Huainan, China; 33 8. Yixin People’s Hospital, Yixin, China; 34 9. Cangzhou Central Hospital, Cangzhou, China;

35 http://bmjopen.bmj.com/ 36 10. Binawaluya Cardiac Center, Jakarta, Indonesia; 37 11. Guangzhou Red Cross Hospital, Guangzhou, China; 38 12. Shanghai Ruijin Hospital, Shanghai, China; 39 13. Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 40 41 China; 42 14. Medistra Hospital, University of Indonesia, Jakarta, Indonesia;

43 15. Gansu Provincial Hospital, Lanzhou, China; on October 1, 2021 by guest. Protected copyright. 44 45 16. Beijing Anzhen Hospital, Capital Medical University, Beijing, China; 46 17. Changshu First People’s Hospital, Changshu, China; 47 18. Cheng-Hsin General Hospital, Taipei, China; 48 49 19. Zhangjiagang First People’s Hospital, ZhangjiaGang, China; 50 20. Changzhou Hospital of Traditional Chinese Medicine, Changzhou, China; 51 21. Jiangxi Provincial People’s Hospital, Nanchang, China; 52 22. Bangkok General Hospital, Bangkok, Thailand; 53 54 23. Xia’Men Zhongshan Hospital, Xia’Men, China; 55 24. Huainan First People’s Hospital, Huainan, China; 56 25. Jintan People’s Hospital, Jintan, China; 57 58 26. Wuxi Third People 's Hospital, Wuxi, China; 59 27. Daqing Oil General Hospital, Daqing, China; 60 28. The Second Hospital of Shandong University, Ji’nan, China;

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29. Xinyang Central Hospital, Xinyang, China; 1 2 30. Fujian Union Hospital, Fuzhou, China; 3 31. Jilin Heart Hospital, Changchun, China; BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 4 32. Otamendi Hospital, Buenos Aires, Argentina; 5 6 33. Chuzhou First People 's Hospital, Chuzhou, China; 7 34. Huainan Xinhua Hospital, Huainan, China; 8 35. Bangle Hospital, Bangkok, Thailand; 9 10 36. Huai’an Second People’s Hospital, Huai’an, China; 11 37. Qingdao Fuwai Hospital, Qingdao, China; 12 38. The Affiliated Hospital of Guangdong Medical University, Guangdong, China; 13 39. University of Turin, Turin, Italy; 14 15 40. The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; 16 41. Xuyi People’s Hospital, Xuyi, China; 17 42. Wuxi Huishan District People’s Hospital, Wuxi, China; 18 For peer review only 19 43. Anqing First People’s Hospital, Anqing, China; 20 44. Liyang Hospital of Traditional Chinese Medicine, Liyang, China; 21 45. Lianyungang Hospital of Traditional Chinese Medicine, Lianyungang, China; 22 23 24 25 26 27 28 29 30 31 32 33 34

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Appendix 3. Institutional Review Boards 1 2 3 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

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1 2 3 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

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Appendix 4. SPIRIT 2013 Checklist 1 2 SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents* 3 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 4 Section/item Ite Description Addressed 5 m on page 6 7 No number 8

9 Administrative information 10 11 Title 1 Descriptive title identifying the study design, population, interventions, and, ____1_____ 12 13 if applicable, trial acronym 14 15 Trial 2a Trial identifier and registry name. If not yet registered, name of intended ____5_____ 16 registration registry 17 18 2b All itemsFor from the peer World Health review Organization Trialonly Registration Data Set ___n/a____ 19 20 Protocol 3 Date and version identifier ___16_____ 21 version 22 23 Funding 4 Sources and types of financial, material, and other support ___16_____ 24 25 Roles and 5a Names, affiliations, and roles of protocol contributors ___15-16__ 26 responsibilitie 5b Name and contact information for the trial sponsor ___16____ 27 s 28 29 5c Role of study sponsor and funders, if any, in study design; collection, 30 31 management, analysis, and interpretation of data; writing of the report; and ___16_____ 32 the decision to submit the report for publication, including whether they will 33 have ultimate authority over any of these activities 34

35 5d Composition, roles, and responsibilities of the coordinating centre, steering ___9-10___ http://bmjopen.bmj.com/ 36 committee, endpoint adjudication committee, data management team, and 37 38 other individuals or groups overseeing the trial, if applicable (see Item 21a 39 for data monitoring committee) 40 41 Introduction 42

43 on October 1, 2021 by guest. Protected copyright. 44 Background 6a Description of research question and justification for undertaking the trial, ____4_____ 45 and rationale including summary of relevant studies (published and unpublished) 46 examining benefits and harms for each intervention 47 48 6b Explanation for choice of comparators ____4_____ 49 50 Objectives 7 Specific objectives or hypotheses ____4_____ 51 52 Trial design 8 Description of trial design including type of trial (eg, parallel group, 53 crossover, factorial, single group), allocation ratio, and framework (eg, ____5_____ 54 superiority, equivalence, noninferiority, exploratory) 55 56 57 Methods: Participants, interventions, and outcomes 58 59 60

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1 Study setting 9 Description of study settings (eg, community clinic, academic hospital) and ___5______2 list of countries where data will be collected. Reference to where list of BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 3 study sites can be obtained 4 5 Eligibility 10 Inclusion and exclusion criteria for participants. If applicable, eligibility ____5_____ 6 criteria criteria for study centres and individuals who will perform the interventions 7 8 (eg, surgeons, psychotherapists) 9 10 Interventions 11a Interventions for each group with sufficient detail to allow replication, ___5-6____ 11 including how and when they will be administered 12 13 11b Criteria for discontinuing or modifying allocated interventions for a given trial ____6_____ 14 participant (eg, drug dose change in response to harms, participant request, 15 or improving/worsening disease) 16 17 11c Strategies to improve adherence to intervention protocols, and any ____6_____ 18 For peer review only 19 procedures for monitoring adherence (eg, drug tablet return, laboratory 20 tests) 21 22 11d Relevant concomitant care and interventions that are permitted or ___6-7____ 23 prohibited during the trial 24 25 Outcomes 12 Primary, secondary, and other outcomes, including the specific 26 measurement variable (eg, systolic blood pressure), analysis metric (eg, ____7_____ 27 change from baseline, final value, time to event), method of aggregation 28 29 (eg, median, proportion), and time point for each outcome. Explanation of 30 the clinical relevance of chosen efficacy and harm outcomes is strongly 31 recommended 32 33 Participant 13 Time schedule of enrolment, interventions (including any run-ins and ____7_____ 34 timeline washouts), assessments, and visits for participants. A schematic diagram is

35 http://bmjopen.bmj.com/ 36 highly recommended (see Figure) 37 38 Sample size 14 Estimated number of participants needed to achieve study objectives and ____8_____ 39 how it was determined, including clinical and statistical assumptions 40 supporting any sample size calculations 41 42 Recruitment 15 Strategies for achieving adequate participant enrolment to reach target ___n/a____

43 sample size on October 1, 2021 by guest. Protected copyright. 44 45 46 Methods: Assignment of interventions (for controlled trials) 47 48 Allocation: 49 50 Sequence 16a Method of generating the allocation sequence (eg, computer-generated ____5_____ 51 generation random numbers), and list of any factors for stratification. To reduce 52 predictability of a random sequence, details of any planned restriction (eg, 53 54 blocking) should be provided in a separate document that is unavailable to 55 those who enrol participants or assign interventions 56 57 Allocation 16b Mechanism of implementing the allocation sequence (eg, central telephone; ___5_____ 58 concealme sequentially numbered, opaque, sealed envelopes), describing any steps to 59 nt conceal the sequence until interventions are assigned 60 mechanism

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1 Implement 16c Who will generate the allocation sequence, who will enrol participants, and ___5______2 ation who will assign participants to interventions 3 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 4 Blinding 17a Who will be blinded after assignment to interventions (eg, trial participants, ___5,7____ 5 (masking) care providers, outcome assessors, data analysts), and how 6 7 17b If blinded, circumstances under which unblinding is permissible, and ___n/a____ 8 procedure for revealing a participant’s allocated intervention during the trial 9 10 11 Methods: Data collection, management, and analysis 12 13 Data 18a Plans for assessment and collection of outcome, baseline, and other trial ____7_____ 14 collection data, including any related processes to promote data quality (eg, duplicate 15 16 methods measurements, training of assessors) and a description of study 17 instruments (eg, questionnaires, laboratory tests) along with their reliability 18 and validity,For if known. peer Reference review to where data only collection forms can be 19 found, if not in the protocol 20 21 18b Plans to promote participant retention and complete follow-up, including list ___n/a____ 22 23 of any outcome data to be collected for participants who discontinue or 24 deviate from intervention protocols 25 26 Data 19 Plans for data entry, coding, security, and storage, including any related ___n/a____ 27 management processes to promote data quality (eg, double data entry; range checks for 28 data values). Reference to where details of data management procedures 29 can be found, if not in the protocol 30 31 Statistical 20a Statistical methods for analysing primary and secondary outcomes. ___8-9____ 32 33 methods Reference to where other details of the statistical analysis plan can be 34 found, if not in the protocol

35 http://bmjopen.bmj.com/ 36 20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ____9_____ 37 38 20c Definition of analysis population relating to protocol non-adherence (eg, as 39 randomised analysis), and any statistical methods to handle missing data ___8-9____ 40 (eg, multiple imputation) 41 42

43 Methods: Monitoring on October 1, 2021 by guest. Protected copyright. 44 45 Data 21a Composition of data monitoring committee (DMC); summary of its role and ____9_____ 46 monitoring reporting structure; statement of whether it is independent from the sponsor 47 48 and competing interests; and reference to where further details about its 49 charter can be found, if not in the protocol. Alternatively, an explanation of 50 why a DMC is not needed 51 52 21b Description of any interim analyses and stopping guidelines, including who ___n/a____ 53 will have access to these interim results and make the final decision to 54 terminate the trial 55 56 Harms 22 Plans for collecting, assessing, reporting, and managing solicited and ___n/a____ 57 58 spontaneously reported adverse events and other unintended effects of trial 59 interventions or trial conduct 60

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1 Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the ___9-10___ 2 process will be independent from investigators and the sponsor 3 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 4

5 Ethics and dissemination 6 7 Research 24 Plans for seeking research ethics committee/institutional review board ___9______8 ethics (REC/IRB) approval 9 approval 10 11 Protocol 25 Plans for communicating important protocol modifications (eg, changes to ___n/a____ 12 amendments eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, 13 14 REC/IRBs, trial participants, trial registries, journals, regulators) 15 16 Consent or 26a Who will obtain informed consent or assent from potential trial participants ___9______17 assent or authorised surrogates, and how (see Item 32) 18 For peer review only 19 26b Additional consent provisions for collection and use of participant data and ___9______20 biological specimens in ancillary studies, if applicable 21 22 Confidentiality 27 How personal information about potential and enrolled participants will be ___n/a____ 23 collected, shared, and maintained in order to protect confidentiality before, 24 25 during, and after the trial 26 Declaration of 28 Financial and other competing interests for principal investigators for the ___16_____ 27 28 interests overall trial and each study site 29 30 Access to 29 Statement of who will have access to the final trial dataset, and disclosure ___9,16___ 31 data of contractual agreements that limit such access for investigators 32 33 Ancillary and 30 Provisions, if any, for ancillary and post-trial care, and for compensation to ___n/a____ 34 post-trial care those who suffer harm from trial participation

35 http://bmjopen.bmj.com/ 36 Dissemination 31a Plans for investigators and sponsor to communicate trial results to ___9______37 policy participants, healthcare professionals, the public, and other relevant groups 38 39 (eg, via publication, reporting in results databases, or other data sharing 40 arrangements), including any publication restrictions 41 42 31b Authorship eligibility guidelines and any intended use of professional writers ___9,16___

43 on October 1, 2021 by guest. Protected copyright. 44 31c Plans, if any, for granting public access to the full protocol, participant-level ___n/a____ 45 dataset, and statistical code 46 47 48 Appendices 49 50 Informed 32 Model consent form and other related documentation given to participants ___9______51 consent and authorised surrogates 52 materials 53 54 Biological 33 Plans for collection, laboratory evaluation, and storage of biological ___n/a____ 55 specimens specimens for genetic or molecular analysis in the current trial and for future 56 57 use in ancillary studies, if applicable 58 59 *It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & 60 Elaboration for important clarification on the items. Amendments to the protocol should be tracked and dated.

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The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons 1 2 “Attribution-NonCommercial-NoDerivs 3.0 Unported” license. 3 BMJ Open: first published as 10.1136/bmjopen-2017-020019 on 6 March 2018. Downloaded from 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

35 http://bmjopen.bmj.com/ 36 37 38 39 40 41 42

43 on October 1, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

16 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Open access Correction

Correction: Treatment effects of systematic two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: rationale and design of a prospective, randomised and multicentre DEFINITION II trial

Zhang J, Gao X, Han Y, et al. Treatment effects of systematic two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: rationale and design of a prospective, randomised and multicentre DEFINITION II trial. BMJ Open 2018;8:e020019. doi: 10.1136/bmjopen-2017-020019.

The sample size estimation in Statistical Analysis Part should be:

From previous studies, we hypothesized that the rate of a 1-year TLF would be 7% in the systematic two-stent technique group and 14% in the provisional stenting group. Accordingly, a total sample size of 600 is needed to detect a power of 0.8 (Type Ⅱ error = 0.2, = 0.05, 2-tailed). Because of the considerable uncertainty, the enrolment is extended to 660 patients (10% increment).

Instead of:

From previous studies, we hypothesized that the rate of a 1-year TLF would be 15% in the systematic two-stent technique group and 25% in the provisional stenting group. Accordingly, a total sample size of 600 is needed to detect a power of 0.8 (Type Ⅱ error = 0.2, = 0.05, 2-tailed). Because of the considerable uncertainty, the enrolment is extended to 660 patients (10% increment).

Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ Open 2018;8:e020019corr1. doi:10.1136/bmjopen-2017-020019corr1

BMJ Open 2018;8:e020019corr1. doi:10.1136/bmjopen-2017-020019corr1 1