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Protocol of the China STEMI Care Project: a 10-year project to improve quality of care by building up the regional STEMI care network ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-026362

Article Type: Protocol

Date Submitted by the 29-Aug-2018 Author:

department of cardiology http://bmjopen.bmj.com/ Zhang, Zheng; The First Hospital of Lanzhou University, department of cardiology Chen, Yu-guo; Shandong University, Department of Emergency Fu, Xianghua; Shanxi Cardiovascular Hospital, department of cardiology Gao, Chuanyu; Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Cardiology Li, Bao; Shanxi Cardiovascular Hospital, department of cardiology Chen, Ji-yan; Guangdong Cardiovascular Institute, Guangdong provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong on September 25, 2021 by guest. Protected copyright. General Hospital, Guangdong Academy of Medical Sciences, Cardiology Wu, Ming; Hainan General Hospital, Department of cardiology Ma, Yitong; The First Affiliated Hospital of Xinjiang Medical University, department of cardiology Zhao, Xingsheng; Inner Mongolia People’s Hospital, department of cardiology Chen, Yundai; Chinese PLA General Hospital, department of cardiology Yan, Hongbing; Fuwai Hospital, Chinese Academy of Medical Sciences, department of cardiology Xiang, Dingcheng; General Hospital of Guangzhou Military Command of PLA, department of cardiology Fang, Weiyi; Shanghai Chest Hospital, department of cardiology Mehta, Sameer; Lumen Foundation Naber, Christoph K; Stent Save a Life Ge, Junbo; Zhongshan Hospital Fudan University, department of cardiology Huo, Yong ; Peking University First Hospital,

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 Accreditation, chest pain center, network, reperfusion, ST-elevation 4 Keywords: myocardial infarction 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 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

32 http://bmjopen.bmj.com/ 33 3. Department of Cardiology, The General Hospital of Shenyang Military, 34 35 Shenyang, Liaoning Province, China 36 37 38 4. Department of Cardiology, The Second Affiliated Hospital Zhejiang University 39

40 School of Medicine, Hangzhou, Zhejiang Province, China on September 25, 2021 by guest. Protected copyright. 41 42 43 5. Department of Cardiology, Kunming General Hospital of Chengdu Military 44 45 Command of PLA, Kunming, Yunnan Department of Cardiology, 46 47 48 6. Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, 49 50 China 51 52 7. Department of Cardiology, The First Hospital of Lanzhou University, Lanzhou, 53 54 55 Gansu Province, China 56 57 1 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 8. Department of Emergency, Qilu Hospital of Shandong University, Jinan, 5 6 Shandong Province, China 7 8 9. Department of Cardiology, The Second Hospital of Hebei Medical University, 9 10 11 Shijiazhuang, Hebei Province, China 12 13 10. Department of Cardiology, Henan Provincial People’s Hospital, Zhengzhou, 14 15 16 Henan Province,For China peer review only 17 18 11. Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi 19 20 21 Province, China 22 23 12. Department of Cardiology, Guangdong General Hospital, Guangzhou, 24 25 26 Guangdong Province, China 27 28 13. Department of Cardiology, Hainan General Hospital, Haikou, Hainan Province, 29 30 China 31

32 http://bmjopen.bmj.com/ 33 14. Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical 34 35 University, Urumchi, The Xinjiang Uygur Autonomous Region, China 36 37 38 15. Department of Cardiology, Inner Mongolia People’s Hospital, Hohhot, The Inner 39

40 Mongolia Autonomous Region, China on September 25, 2021 by guest. Protected copyright. 41 42 43 16. Department of Cardiology, Chinese PLA General Hospital, Beijing, China 44 45 17. Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical 46 47 48 Sciences, Beijing, China 49 50 18. Department of Cardiology, General Hospital of Guangzhou Military Command of 51 52 PLA, Guangzhou, Guangdong Province, China 53 54 55 19. Department of Cardiology, Shanghai Chest Hospital, Shanghai, China 56 57 2 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 20. Lumen Foundation, Miami, USA 5 6 21. Stent Save a Life, Paris, France 7 8 22. Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 9 10 11 China 12 13 14 15 16 Running title:For Protocol peer of 10year Chinareview STEMI Care Projectonly 17 18 19 20 21 Corresponding author: Yong Huo, MD 22 23 Peking University First Hospital, Department of Cardiology 24 25 26 8 Xishiku St, Xicheng District, Beijing, China, 100035 27 28 Email: [email protected] 29 30 Phone: 861083572283 31

32 http://bmjopen.bmj.com/ 33 Fax: 861066137748 34 35 36 37 38 Date: 39

40 This project was initialed in 2011 and will be finished in 2021. on September 25, 2021 by guest. Protected copyright. 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 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 Abstract 5 6 Introduction: The China STEMI (STelevation myocardial infarction) Care Project 7 8 (CSCAP) aimed to improve the reperfusion treatment rate and shorten the total 9 10 11 duration of myocardial ischemia by establishing a regional STEMI treatment network 12 13 covering the whole city region, whole city population, and whole disease processes 14 15 16 step by step.For peer review only 17 18 Methods and analysis: This is a prospective, multicenter registry involving three 19 20 21 stages. And the CSCAP included 18 provinces, 4 municipalities, and 2 autonomous 22 23 regions in China. Patients with STEMI who met with the third acute myocardial 24 25 26 infarction definition of 2012 and the Chinese STEMI diagnosis and treatment 27 28 guidelines were enrolled. Phase 1 focused on the inhospital process optimization of 29 30 primary percutaneous coronary intervention (PPCI) hospitals; phase 2 on the PPCI 31

32 http://bmjopen.bmj.com/ 33 hospitalbased regional STEMI transfer network, including emergency medical 34 35 services and nonPPCI hospitals; and phase 3 on the wholecity STEMI care network 36 37 38 construction by promoting chest pain center accreditation. Systematic data collection, 39

40 assessment of quality of care, and subsequent improvement were implemented on September 25, 2021 by guest. Protected copyright. 41 42 43 throughout the project to continuously improve the quality of care for patients with 44 45 STEMI in the project. 46 47 48 Ethics and dissemination: CSCAP, with the establishment of an intrinsic feedback 49 50 and certification system, will provide a tailored and continuous quality of STEMI care 51 52 improvement plan based on the conditions of different regions to further integrate the 53 54 55 STEMI care network nationwide. 56 57 4 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 5 6 Key words: Accreditation, chest pain center, network, reperfusion, STelevation 7 8 myocardial infarction 9 10 11 12 13 Strengths and limitations of this study 14 15 16 CSCAP is theFor first project peer that focused review on establishing aonly regional STEMI emergency 17 18 care network in China, which will help to understand the condition of STEMI care in 19 20 21 China extensively. Moreover, quality of STEMI care will be optimized through 22 23 inhospital process optimization, PPCI hospitalbased regional STEMI transfer 24 25 26 network construction, and the wholecity STEMI care network construction step by 27 28 step. However, hospitals in CSCAP were not randomly selected, which might be 29 30 because of lack of representatives to some degree. Alternatively, it will provide a 31

32 http://bmjopen.bmj.com/ 33 tailored quality of care improvement plan based on the conditions of different regions. 34 35 36 37 38 39

40 on September 25, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 5 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 Introduction 5 6 The disease burden of cardiovascular diseases is increasing, posing a major 7 8 public health issue in China. China will have another 75 million patients with 9 10 11 myocardial infarction in the next 15 years with the increasing risk factors and aging 12 13 population [1]. The Chinese cardiovascular report in 2016 showed an increase in both 14 15 16 the hospitalizationFor ratio peer and mortality review of acute myocardial only infarction (AMI) over the 17 18 years. The mortality of AMI is higher in rural areas than in the city, and the younger 19 20 21 population is most vulnerable [2]. 22 23 Acute STelevation myocardial infarction (STEMI), mainly caused by a sudden 24 25 26 obstruction of the coronary artery with thrombus, benefits from both increasing 27 28 reperfusion rate and shortening of the duration from the symptom occurrence to the 29 30 opening of the target vessel [3 4]. Although implementing evidencebased medicine 31

32 http://bmjopen.bmj.com/ 33 significantly improves the prognosis of patients with STEMI, the gap of the 34 35 translational application is still large in realworld settings [5]. A majority of Chinese 36 37 38 patients with STEMI miss the optimal treatment timing due to restrictions from both 39

40 patients and medical services [6]. Additionally, the ratio of significant deficiency in on September 25, 2021 by guest. Protected copyright. 41 42 43 STEMI reperfusion treatment remained at the level of around 55% in the last decade; 44 45 hence, the inhospital mortality has not changed significantly yet [7]. 46 47 48 The effective treatment of STEMI is a systematic issue, and the solution is neither 49 50 a novel thrombolytic drug nor an intervention device. It can be brought about by 51 52 comprehensive factors, including patient health awareness, physician level, 53 54 55 physician–patient relationship, medical reimbursement system, prehospital emergency 56 57 6 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 system, inhospital treatment, connection mechanism between prehospital and 5 6 inhospital care, and posthospital management. Successful experiences from both 7 8 American Lifeline program and the European Stent – Save a Life can be used for 9 10 11 reference. The quality of medical service can be significantly improved when regional 12 13 STEMI care network is established through close collaboration at different levels of 14 15 16 hospitals andFor the emergency peer medical review system (EMS) [8 9]. only 17 18 China has gradually increased the input of medical insurance in the last few 19 20 21 decades. However, how to implement the best treatment for STEMI, keeping in mind 22 23 the differences in geographical, humanistic, and medical insurance policy coverage, 24 25 26 still needs to be discussed. At present, little information exists about whether the 27 28 foreign STEMI guide is difficult to be widely used in China because of the differences 29 30 between the East and the West. Therefore, more evidence from China is needed. 31

32 http://bmjopen.bmj.com/ 33 Although largescale studies on AMI or acute coronary syndrome (ACS), such as 34 35 CPACS, CCC, ChinaPEACE, and CAMI, have been conducted in China, none 36 37 38 focused on establishing a regional STEMI emergency care network [7 1012]. Serial 39

40 documents issued by the National Health Commission of China provided favorable on September 25, 2021 by guest. Protected copyright. 41 42 43 government support and further emphasized the importance of the administrative 44 45 departments of health care at all levels in strengthening the construction of the 46 47 48 regional emergency medical treatment system [1315]. 49 50 This study aimed to introduce the protocol of a 10year project named as China 51 52 STEMI Care Project (CSCAP), including objective, organization, procedures, data 53 54 55 collection, assessment and feedback, and updates. The results provided important 56 57 7 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 evidence for the improvement in STEMI care within the whole region and also useful 5 6 information when building up STEMI network in other similar regions. 7 8 9 10 11 Methods and analysis 12 13 Objectives 14 15 16 CSCAP For aimed to peer build up different review types of integrated only regional STEMI care 17 18 network covering the whole city region, city population, and disease processes 19 20 21 according to different conditions nationwide. It also aimed to improve the awareness 22 23 of public health and emergency treatment for patients with STEMI, increase the ratio 24 25 26 of reperfusion treatment, shorten the overall duration of myocardial ischemia, and 27 28 implement standard secondary prevention to improve the longterm prognosis through 29 30 the establishment and optimization of medical care assessment and feedback system 31

32 http://bmjopen.bmj.com/ 33 with data support. 34 35 Study design 36 37 38 CSCAP was a prospective, multicenter registry involving three stages. Phase 1 of 39

40 CSCAP (CSCAP1) focused on the inhospital process optimization of primary on September 25, 2021 by guest. Protected copyright. 41 42 43 percutaneous coronary intervention (PPCI) hospitals. Phase 2 of CSCAP (CSCAP2) 44 45 focused on the PPCI hospitalbased regional STEMI transfer network construction 46 47 48 with their adjacent nonPPCI hospitals and EMS. Phase 3 of CSCAP (CSCAP3) 49 50 focused on the wholecity STEMI care network construction by promoting chest pain 51 52 center (CPC) accreditation (Figure 1). Systematic data collection, assessment of 53 54 55 quality of care, and subsequent improvement were implemented throughout this study 56 57 8 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 to continuously improve the quality of care. 5 6 Organizational framework 7 8 CSCAP was established by the Chinese Physician Association and supported by 9 10 11 the National Health Commission of China in 2011. After collaborating with the 12 13 European Stent – Save a Life in CSCAP3, China became its member country in 2017. 14 15 16 The project officeFor and peersteering committee review were set up foronly management and academic 17 18 support. Data management and statistical analyses were conducted by the School of 19 20 21 Public Health of Peking University. 22 23 Site selection 24 25 26 CSCAP included 18 provinces (Anhui, Fujian, Gansu, Guangdong, Guangxi, 27 28 Hainan, Hebei, Heilongjiang, Henan, Hubei, Jiangsu, Liaoning, Shandong, Shanxi, 29 30 Sichuan, and Zhejiang), 4 municipalities (Beijing, Chongqing, Shanghai, Tianjin, and 31

32 http://bmjopen.bmj.com/ 33 Yunnan), and 2 autonomous regions (Xinjiang and Inner Mongolia) because of the 34 35 high incidence of STEMI in North China and economic issues in South China (Figure 36 37 38 2). 39

40 A total of 53 tertiary hospitals qualified for PPCI in 14 on September 25, 2021 by guest. Protected copyright. 41 42 43 provinces/municipalities/autonomous regions of China enrolled in CSCAP1 44 45 (Appendix table 1). These hospitals were selected because they were at the top level 46 47 48 in their city and potentially a hub for regional network construction in CSCAP2. A 49 50 total of 241 PCI hospitals with hundreds of adjunct nonPCI hospitals from 24 51 52 provinces/municipalities/autonomous regions were selected to establish the regional 53 54 55 STEMI care network in CSCAP2 (Appendix table 1). A total of seven cities (Harbin, 56 57 9 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 Hangzhou, Nanning, Qingdao, Shenzhen, Suzhou, and Taiyuan) according to two 5 6 different EMS types were selected to build up the wholecity STEMI care network in 7 8 CSCAP3 (Figure 2). 9 10 11 Patient enrollment and follow-up 12 13 Patients with STEMI who met with the third AMI definition in 2012 and the 14 15 16 Chinese STEMIFor diagnosis peer and treatment review guidelines were only enrolled [16 17]. All patients 17 18 received routine clinical assessments and treatments without any experimental 19 20 21 intervention. The study was reviewed and approved by the Ethics Board at Peking 22 23 University First Hospital. 24 25 26 In CSCAP1, a total of 4191 patients admitted to hospitals, with symptom onset 27 28 within 12 h regardless of whether receiving reperfusion or symptom onset within 29 30 12–24 h needing PPCI, were enrolled consecutively in 2012. In CSCAP2, a total of 31

32 http://bmjopen.bmj.com/ 33 20,810 patients with STEMI occurrence within 30 days regardless of reperfusion were 34 35 enrolled consecutively from PPCI hospitals three times at 6month intervals during 36 37 38 2015 to 2017. In CSCAP3, a total of 30 hospitalized patients with symptom onset 39

40 within 30 days were enrolled consecutively from each hospital every 3 months. on September 25, 2021 by guest. Protected copyright. 41 42 43 Patients with STEMI were enrolled consecutively from the whole network units, 44 45 including both PCI and nonPCI hospitals. The patients who survived after hospital 46 47 48 discharge were also followed up for 1 year. 49 50 Procedures 51 52 The treatment flow of the patients with STEMI was based on the STEMI protocol 53 54 55 of the Announcement of Improving Medical Emergency Treatment Performance of 56 57 10 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 Acute Cardiovascular and Cerebrovascular Diseases released by the National Health 5 6 Commission of China in 2015 [15]. Briefly, this flow chart included 1 center (EMS), 7 8 2 types of hospitals (PCI and nonPCI), 3 types of transport methods (EMS to hospital, 9 10 11 bypass emergency department (ED), and interhospital), and 11 clinical pathways. 12 13 Different clinical pathways were selected to execute the optimal emergency treatment 14 15 16 based on theFor visiting time,peer method, andreview hospital level (Figure only 3). According to typical 17 18 ischemic symptoms and electrocardiogram (ECG), the procedure was started without 19 20 21 results of myocardial biomarkers in case of delay. 22 23 Data collection and management 24 25 26 CSCAP collected data of all treatment flow, which were entered into a selfbuilt 27 28 electronic database together with two existing databases of both CPC accreditation 29 30 and national PCI registry by trained clinical research coordinators and clinicians in 31

32 http://bmjopen.bmj.com/ 33 each hospital. Variables included general information of patients, prehospital EMS 34 35 treatment, inhospital management, and followup management (Table 1). The data 36 37 38 quality was monitored, and suspicious contents by review mainly included missing, 39

40 outlier, and logical error data. When all problems were resolved, the database was on September 25, 2021 by guest. Protected copyright. 41 42 43 locked for statistical analysis. 44 45 Key performance index for evaluating the quality of medical care 46 47 48 CSCAP mainly used the describing method to rank data quality and medical 49 50 quality. Continuous variables were described as mean (standard deviation) or median 51 52 (interquartile range), while categorical variables were described as percentage. The 53 54 55 multivariate regression model was used to evaluate the factors related to the 56 57 11 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 assessment of medical quality. The Cox model was used to analyze the association 5 6 between the exposures and medical outcomes. A P value <0.05 was defined as a 7 8 significant difference. All analyses were performed using R 9 10 11 (http://www.Rproject.org). 12 13 A total of 13 primary key performance indexes (KPIs) were selected for medical 14 15 16 quality evaluationFor based peer on different review roles of EMS and hospitalsonly with or without PCI 17 18 capability in STEMI treatment (Table 2). The circular 19 20 21 enrollment–evaluation–improvement method was implemented in both CSCAP2 and 22 23 CSCAP3. Comparison of KPIs with itself and others was conducted for tailed 24 25 26 improvements. Quality feedback report contained each KPI of the affiliation and its 27 28 ranking among all affiliations and all regional affiliations, which was presented as 29 30 location in quartile interval without ranking results of others. 31

32 http://bmjopen.bmj.com/ 33 34 35 Ethics and dissemination 36 37 38 CSCAP was the first prospective registry study on the establishment of STEMI 39

40 regional care network in China step by step, covering the whole city, population, and on September 25, 2021 by guest. Protected copyright. 41 42 43 treatment processes. Some largescale ACS registry studies have been carried out in 44 45 China, such as the CCC program focusing on the inhospital treatment of ACS [11], 46 47 48 the CPACS study focusing on the ACS clinical pathway [10], the CAMI study 49 50 focusing on the hospital treatment of STEMI and nonSTelevation myocardial 51 52 infarction (NSTEMI) [12], and the ChinaPEACE study (retrospective study) [7]. 53 54 55 Different from these studies, CSCAP prospectively collected data to analyze the 56 57 12 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 whole process of STEMI treatment and then provided feedback to units for 5 6 problemguided improvement. This study helped understand the condition of STEMI 7 8 care in China extensively, the gap and differences with other countries, and the issues 9 10 11 and solutions, leading to optimized clinical practice and improved medical quality. 12 13 An integrated regional network mainly contains PCI hospital, nonPCI hospital, 14 15 16 and EMS. TheFor medical peer system and review patient factors together only determine the delay in 17 18 STEMI emergency treatment [18]. Three major types of EMS exist in China: (1) 19 20 21 independenttype EMS, which has its own ambulances, (2) commandtype EMS, 22 23 which does not have its own ambulances and uses local hospital ambulances, and (3) 24 25 26 affiliatetype EMS, which is based in hospitals and uses its ambulances. On the basis 27 28 of these comprehensive situations, patients may not be transported to the optimal 29 30 hospital to receive effective treatment in the shortest period because of incomplete 31

32 http://bmjopen.bmj.com/ 33 communication [19]. Thus, different types of prehospital information transmission 34 35 should be considered accordingly for hospital alert and rapid and accurate transport. 36 37 38 Optimizing the inhospital green channel can significantly shorten the 39

40 doortoballoon (D2B) duration, while establishing a CPC was one of the most on September 25, 2021 by guest. Protected copyright. 41 42 43 important methods [20 21]. Integration of multiple resources can help in early 44 45 diagnosis, risk stratification, and treatment of STEMI and other acute chest 46 47 48 pain–related diseases, thus improving efficiency, prognosis, and medical burden. 49 50 Traditional CPC focuses on the optimization and integration of the inhospital green 51 52 channel aimed to shorten D2B time in STEMI care. The concept of a modern CPC in 53 54 55 STEMI care expands to establish an effective regional emergency treatment network 56 57 13 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 aimed to shorten the total ischemia duration, thus maximizing the advantage of 5 6 reperfusion therapy. Medical system and patient factors together determine the delay 7 8 of STEMI emergency treatment [18]. Public education for selfawareness 9 10 11 improvement, which is one of the elements of the CPC construction, could enable 12 13 patients to seek medical assistance promptly in case of suspected myocardial 14 15 16 infarction, acceptFor timely peer reperfusion review without hesitation, only and adhere to primary and 17 18 secondary prevention. CPC independent accreditation in China was initiated in 2013 19 20 21 with support from the National Health and Family Planning Commission and directed 22 23 by the Chinese Society of Cardiology and the Chinese Physician Association. Two 24 25 26 types of CPC accreditation standards were developed [22 23], which were separately 27 28 applicable to PCI hospitals and nonPCI hospitals or to relatively small PCI hospitals 29 30 not able to reach the PCI scale. The first standard focused on the improvement in the 31

32 http://bmjopen.bmj.com/ 33 emergency PCI capacity and efficiency, while the second one focused on the 34 35 improvement in thrombolysis and referral capacity to PPCI hospitals. Currently, 460 36 37 38 accredited CPCs and 2721 hospitals were in the waiting list in China by April 2018. 39

40 Rapid identification of STEMI and referral to a hospital without PCI certification on September 25, 2021 by guest. Protected copyright. 41 42 43 are also important segments in establishing a regional STEMI emergency treatment 44 45 system. A large number of patients with coronary heart disease in China are 46 47 48 distributed in rural areas, and the mortality of AMI in these regions surpasses the 49 50 urban areas. Although PPCI is the most effective treatment for STEMI, its 51 52 implementation is difficult in most of the primary hospitals, which are limited by 53 54 55 medical condition, geographic location, and techniques. On the basis of these 56 57 14 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 conditions of China, early thrombolysis and transfer PCI strategy are the priorities in 5 6 most of the primary hospitals. Therefore, establishing an effective regional 7 8 collaboration emergency treatment network to improve the treatment quality of 9 10 11 STEMI is extremely important. 12 13 The National Cardiovascular Data Registry (NCDR), established since 1997, has 14 15 16 become the For basis for peer project implementation review and qualityonly evaluation as well as 17 18 research center medical quality improvement in the United States. It has a positive 19 20 21 impact on the clinical practice, medical payment, clinical research, and government 22 23 decisionmaking [24 25]. The present study referred to the NCDR model to optimize 24 25 26 the STEMI medical quality and established an assessment and feedback system for 27 28 KPIs, such as efficiency of emergency transport, efficiency of hospital treatment with 29 30 various levels, and cooperation between network units. For KPI selection, PPCI 31

32 http://bmjopen.bmj.com/ 33 hospitals focused on the improvement in the emergency PCI capacity and efficiency; 34 35 nonPPCI hospitals focused on the improvement in rapid diagnosis, thrombolysis, and 36 37 38 referral capacity to PPCI hospitals; and EMS focused on the improvement in 39

40 information transmission to alert hospitals early for rapid and accurate transport. on September 25, 2021 by guest. Protected copyright. 41 42 43 Since China has a large number of patients, its cardiovascular clinical data 44 45 resource is the largest in the world. However, Chinese guidelines lack highquality 46 47 48 evidence. Clinical practice has demonstrated that overseas guidelines and evidence 49 50 may not be applicable to the prevention and treatment of cardiovascular diseases in 51 52 the Chinese population [26]. CSCAP established a database platform for the STEMI 53 54 55 wholetreatment process, including primary prevention, emergency treatment, 56 57 15 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 inhospital treatment, and secondary prevention. It was a realworld registry study and 5 6 provided additional information. For example, this study evaluated the compliance of 7 8 other related cardiovascular guidelines in real clinical practice, tracked the efficacy 9 10 11 and side effects of novel drugs and devices, provided evidence for new guidelines, 12 13 and compared differences among various hospitals and regions. 14 15 16 However,For the present peer study had reviewsome limitations. First,only CSCAP was expected to 17 18 record clinical information of the fulltreatment procedure of STEMI, which involved 19 20 21 many affiliations and departments. Considering the real situation in ED, many time 22 23 points of the KPIs could not be recorded manually on time, which might have led to 24 25 26 missing and inaccurate data. Mobile device app could record the time variables 27 28 through a simple click and completed the prehospital ECG transmission. Additionally, 29 30 the auto capture of data gradually became possible to resolve this issue. All of these 31

32 http://bmjopen.bmj.com/ 33 were considered in this study. Second, hospitals in CSCAP1 and CSCAP2 were not 34 35 strictly selected according to the radio of PPCI, which might be because of lack of 36 37 38 representatives to some degree. The selected hospitals with good conditions were 39

40 better than the average level in their region. However, the first two phases of CSCAP on September 25, 2021 by guest. Protected copyright. 41 42 43 were not only a description of the current situation of STEMI treatment, but a project 44 45 to improve the quality of medical care. Therefore, highlevel PCI hospitals were 46 47 48 suitable to be used as core centers to establish the regional network. These successful 49 50 experiences might have referral relevance to hospitals in the same region but outside 51 52 this study, which might be useful for the wholecity network construction in 53 54 55 CSCAP3. 56 57 16 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 Shortening of the overall ischemia duration and increase in the reperfusion 5 6 treatment rate are critical issues and challenges in STEMI care. The integration and 7 8 optimization of a systemic STEMI collaborative network with government support are 9 10 11 urgent issues that need to be resolved in China. CSCAP, with the establishment of an 12 13 intrinsic feedback and certification system, will provide important prospective 14 15 16 information For for the networkpeer construction review from PPCI only hospitalcentered regional 17 18 network to wholecity covered STEMI transfer network step by step to establish an 19 20 21 optimal STEMI care system in China. 22 23 24 25 26 Authors’ contributions 27 28 Yan Zhang coordinated the study, assisted with data collection, performed data 29 30 analysis, and drafted the manuscript. Bo Yu, Yaling Han, Jianan Wang, Lixia Yang, 31

32 http://bmjopen.bmj.com/ 33 Zheng Wan, Zheng Zhang, Yuguo Chen, Xianghua Fu, Chuanyu Gao, Bao Li, Jiyan 34 35 Chen, Ming Wu, Yitong Ma, Xingsheng Zhao, Yundai Chen, Hongbing Yan, 36 37 38 Dingcheng Xiang, Weiyi Fang, and Junbo Ge carried out the data collection, and 39

40 helped to draft the manuscript. Sameer Mehta and Christoph K participated in the on September 25, 2021 by guest. Protected copyright. 41 42 43 design and helped to analyze data and draft the manuscript. Naber, Yong Huo, PI of 44 45 the project, conceived and designed the project, helped to collect data and draft the 46 47 48 manuscript. All authors reviewed the results and approved the final version of the 49 50 manuscript. 51 52 53 54 55 56 57 17 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 Funding 5 6 CSCAP was funded by SanofiAventis, Abbott, and AstraZeneca. 7 8 9 10 11 Conflicts of interest 12 13 The authors declare no conflicts of interest. 14 15 16 For peer review only 17 18 Acknowledgments 19 20 21 The authors thank the members of the study team of all collaborative hospitals 22 23 and emergency medical services. They are also grateful to the organizations Chinese 24 25 26 Medical Doctor Association and China Cardiovascular Association and acknowledge 27 28 the support provided by the National Health Commission and local governments in 29 30 China. 31

32 http://bmjopen.bmj.com/ 33 34 35 Patient consent 36 37 38 Obtained. 39

40 on September 25, 2021 by guest. Protected copyright. 41 42 43 Ethics approval 44 45 The study was reviewed and approved by the Ethics Board at Peking University 46 47 48 First Hospital. 49 50 51 52 Data sharing statement 53 54 55 No additional data are available. 56 57 18 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 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 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 25, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 19 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 References 5 6 1. Stevens W, Peneva D, Li JZ, et al. Estimating the future burden of cardiovascular 7 8 disease and the value of lipid and blood pressure control therapies in China. 9 10 11 BMC health services research 2016;16:175. 12 13 2. Report on cardiovascular disease in China: Encyclopedia of China Publishing 14 15 16 house,For 2016. peer review only 17 18 3. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the 19 20 21 management of STelevation myocardial infarction: a report of the American 22 23 College of Cardiology Foundation/American Heart Association Task Force on 24 25 26 Practice Guidelines. Circulation 2013;127:e362425. 27 28 4. Task Force on the management of STseamiotESoC, Steg PG, James SK, et al. ESC 29 30 Guidelines for the management of acute myocardial infarction in patients 31

32 http://bmjopen.bmj.com/ 33 presenting with STsegment elevation. European heart journal 34 35 2012;33:2569619. 36 37 38 5. Eagle KA, Nallamothu BK, Mehta RH, et al. Trends in acute reperfusion therapy 39

40 for STsegment elevation myocardial infarction from 1999 to 2006: we are on September 25, 2021 by guest. Protected copyright. 41 42 43 getting better but we have got a long way to go. European heart journal 44 45 2008;29:60917. 46 47 48 6. Song L, Hu DY, Yan HB, et al. Influence of ambulance use on early reperfusion 49 50 therapies for acute myocardial infarction. Chinese medical journal 51 52 2008;121:7715. 53 54 55 7. Li J, Li X, Wang Q, et al. STsegment elevation myocardial infarction in China 56 57 20 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 from 2001 to 2011 (the China PEACERetrospective Acute Myocardial 5 6 Infarction Study): a retrospective analysis of hospital data. Lancet 7 8 2015;385:44151. 9 10 11 8. Jollis JG, Granger CB, Henry TD, et al. Systems of care for STsegmentelevation 12 13 myocardial infarction: a report From the American Heart Association's 14 15 16 Mission:For Lifeline. peer Circulation. review Cardiovascular only quality and outcomes 17 18 2012;5:4238. 19 20 21 9. Kristensen SD, Fajadet J, Di Mario C, et al. Implementation of primary angioplasty 22 23 in Europe: stent for life initiative progress report. EuroIntervention : journal of 24 25 26 EuroPCR in collaboration with the Working Group on Interventional 27 28 Cardiology of the European Society of Cardiology 2012;8:3542. 29 30 10. Gao R, Patel A, Gao W, et al. Prospective observational study of acute coronary 31

32 http://bmjopen.bmj.com/ 33 syndromes in China: practice patterns and outcomes. Heart 2008;94:55460. 34 35 11. Hao Y, Liu J, Liu J, et al. Rationale and design of the Improving Care for 36 37 38 Cardiovascular Disease in China (CCC) project: A national effort to prompt 39

40 quality enhancement for acute coronary syndrome. American heart journal on September 25, 2021 by guest. Protected copyright. 41 42 43 2016;179:10715. 44 45 12. Xu H, Li W, Yang J, et al. The China Acute Myocardial Infarction (CAMI) 46 47 48 Registry: A national longterm registryresearcheducation integrated platform 49 50 for exploring acute myocardial infarction in China. American heart journal 51 52 2016;175:193201 e3. 53 54 55 13. Prehospital medical emergency management measures. Chinese Village Medicine 56 57 21 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 2014:8586. (In Chinese) 5 6 14. National Health Commission of China. Guiding Principles for Construction and 7 8 Management of Chest Pain Center (Trial). 2017. (In Chinese) 9 10 11 15. National Health Commission of China. The Announcement of Improving Medical 12 13 Emergency Treatment Performance of Acute Cardiovascular and 14 15 16 CerebrovascularFor peer Diseases. 2015. review (In Chinese) only 17 18 16. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial 19 20 21 infarction. Circulation 2012;126:202035. 22 23 17. Chinese Society of Cardiology, Editorial board of Chinese Journal of Cardiology. 24 25 26 Guidelines for the diagnosis and treatment of acute ST segment elevation 27 28 myocardial infarction. Chin J Cardiol 2015;43:38093. 29 30 18. Windecker S, Bax JJ, Myat A, et al. Future treatment strategies in STsegment 31

32 http://bmjopen.bmj.com/ 33 elevation myocardial infarction. Lancet 2013;382:64457. 34 35 19. Ranasinghe I, Rong Y, Du X, et al. System barriers to the evidencebased care of 36 37 38 acute coronary syndrome patients in China: qualitative analysis. Circulation. 39

40 Cardiovascular quality and outcomes 2014;7:20916. on September 25, 2021 by guest. Protected copyright. 41 42 43 20. Bradley EH, Herrin J, Wang Y, et al. Strategies for reducing the doortoballoon 44 45 time in acute myocardial infarction. The New England journal of medicine 46 47 48 2006;355:230820. 49 50 21. Graff LG, Dallara J, Ross MA, et al. Impact on the care of the emergency 51 52 department chest pain patient from the chest pain evaluation registry 53 54 55 (CHEPER) study. The American journal of cardiology 1997;80:5638. 56 57 22 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 22. China Chest Pain Center Accreditation Work Committee. Standard for Chinese 5 6 Chest Pain Center accreditation. Chin J Intervent Cardiol 2016;24:12130. 7 8 23. China Chest Pain Center Accreditation Work Committee. Standard for Chinese 9 10 11 Primary Chest Pain Center accreditation. Chin J Intervent Cardiol 12 13 2016;24:13133. 14 15 16 24. Diercks ForDB, Kontos peer MC, Chen reviewAY, et al. Utilization only and impact of prehospital 17 18 electrocardiograms for patients with acute STsegment elevation myocardial 19 20 21 infarction: data from the NCDR (National Cardiovascular Data Registry) 22 23 ACTION (Acute Coronary Treatment and Intervention Outcomes Network) 24 25 26 Registry. Journal of the American College of Cardiology 2009;53:1616. 27 28 25. Krim SR, Vivo RP, Krim NR, et al. Regional differences in clinical profile, quality 29 30 of care, and outcomes among Hispanic patients hospitalized with acute 31

32 http://bmjopen.bmj.com/ 33 myocardial infarction in the Get with GuidelinesCoronary Artery Disease 34 35 (GWTGCAD) registry. American heart journal 2011;162:98895 e4. 36 37 38 26. Huo Y, Li J, Qin X, et al. Efficacy of folic acid therapy in primary prevention of 39

40 stroke among adults with hypertension in China: the CSPPT randomized on September 25, 2021 by guest. Protected copyright. 41 42 43 clinical trial. Jama 2015;313:132535. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 23 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 Table 1. CSCAP data elements 5 6 Category Example elements 7 8 9 Patient baseline information Demographics (age, sex, ethnicity, occupation, marriage 10 11 status, medical insurance, and status) 12 13 Risk factors (smoking status, BMI, hypertension, diabetes, 14 15 16 For peerdyslipidemia, review peripheral artery only disease, prior MI history, prior 17 18 stroke history, and prior revascularization) 19 20 21 Clinical presentation (blood pressure, heart rate, and cardiac 22 23 function classification) 24 25 26 Prehospital information Patient (symptoms, symptom onset time, first medical contact 27 28 method/time, and hospital approaching method) 29 30 31 EMS (response time, transfer process, first ECG time, ECG

32 http://bmjopen.bmj.com/ 33 transmission ratio, and bypass ED) 34 35 NonPCI hospital (admission time, first ECG time, diagnosis 36 37 38 process, reperfusion and other treatment, DIDO time, and 39

40 transfer process) on September 25, 2021 by guest. Protected copyright. 41 42 43 PCI hospital information Reperfusion (primary PCI, thrombolysis, pharmacoinvasive 44 45 method and postthrombolysis PCI, 46 47 48 indication/contraindication, and nonreperfusion reasons) 49 50 Treatment delay (hospital approaching method, ED/chest pain 51 52 53 center, bypass ED, admission time, first ECG time, catheter 54 55 lab ready time, D2B, D2N, FMC2B, total ischemic time, and 56 57 24 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 reasons of delay) 5 6 PCI procedures (operative route, coronary angiography 7 8 results, aspiration, culprit vessels, aspiration, stent, and 9 10 11 elective PCI) 12 13 Thrombolytic procedures (thrombolytic agent, dose, and 14 15 16 For peeroutcome) review only 17 18 Medications (loading dose DAPT/statin, antiplatelets, 19 20 21 βblockers, statin, ACEI/ARB, GP IIb/IIIa inhibitor, and 22 23 anticoagulant with dose and contraindication information) 24 25 26 Laboratory results (Troponin, CKMB, creatinine, 27 28 hemoglobin, HbA1C, glucose, BNP, NTproBNP, lipids, and 29 30 UCG) 31

32 http://bmjopen.bmj.com/ 33 Discharge (diagnosis, inhospital duration, cost, and 34 35 medications) 36 37 38 Outcomes (death, nonfatal reinfarction, bleeding, nonfatal 39

40 stroke, revascularization, and mechanical complication) on September 25, 2021 by guest. Protected copyright. 41 42 43 Followup and management Presentation status (symptom, cardiac function classification, 44 45 blood pressure, heart rate, and followup on time ratio) 46 47 48 Laboratory results (lipid profiles, glucose traits, HbA1c, 49 50 creatinine, hemoglobin, BNP, NTproBNP, ECG, and UCG) 51 52 Medications (antiplatelets, βblockers, statin, and ACEI/ARB) 53 54 55 Risk factor control rate (BP, lipid, glucose, and smoking 56 57 25 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 cessation)Outcomes (death, nonfatal reinfarction, stroke, 5 6 revascularization, rehospitalization due to unstable angina 7 8 pectoris, heart failure or other cardiovascular reasons, and 9 10 11 bleeding) 12 13 ACEI, Angiotensinconverting enzyme inhibitor; ARB, angiotensin receptor blocker; 14 15 16 BMI, body massFor index; peer BNP, brain reviewnatriuretic peptide; onlyCKMB, creatine kinase MB 17 18 isoenzyme; DAPT, dual antiplatelet therapy; D2B, door to balloon; D2N, door to 19 20 21 needle; DI–DO, door in–door out; ECG, electrocardiograph; ED, emergency 22 23 department; EMS, emergency medical service; FMC2B, first medical contact to 24 25 26 balloon; GP IIb/IIIa, glycoprotein IIb/IIIa; HbA1c, glycosylated hemoglobin A1c; MI, 27 28 myocardial infarction; NTProBNP, Nterminal pro–brain natriuretic peptide; PCI, 29 30 percutaneous coronary intervention; UCG, ultrasound cardiogram. 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 25, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 26 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 Table 2. Primary performance measures for medical care quality evaluation 5 6 Primary performance measures 7 8 9 Prehospital care 10 11 Symptom onset to arrival in hospital (min) 12 13 Hospital admission ratio via ambulance (%) 14 15 16 Prehospital ECG Fortransmission peer ratio (%) review only 17 18 Bypass ED ratio in patients with symptom onset within 12 h (%) 19 20 21 Reperfusion 22 23 Overall reperfusion ratio (%) 24 25 26 Thrombolysis ratio in patients with symptom onset within 12 h (%) 27 28 Primary PCI ratio in patients with symptom onset within 12 h (%) 29 30 31 D2B in patients with symptom onset within 12 h (min)

32 http://bmjopen.bmj.com/ 33 D2N in patients with symptom onset within 12 h (min) 34 35 Discharge 36 37 38 Usage of both DAPT, statin, β blocker, and ACEI/ARB in patients without contraindication (%) 39

40 Outcomes on September 25, 2021 by guest. Protected copyright. 41 42 43 Inhospital mortality (%) 44 45 Follow-up and management 46 47 48 1Year ontime followup ratio (%) 49 50 1Year MACE (%) including mortality, nonfatal myocardial infarction, nonfatal stroke, 51 52 53 hospitalization due to heart failure or acute coronary syndrome, etc. 54 55 ACEI, Angiotensinconverting enzyme inhibitor; ARB, angiotensin receptor blocker; 56 57 27 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 DAPT, dual antiplatelet therapy; D2B, door to balloon; D2N, door to needle; ECG, 5 6 electrocardiogram; ED, emergency department; PCI, percutaneous coronary 7 8 intervention; MACE, major adverse cardiovascular event. 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 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 25, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 28 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 4 Figure legends 5 6 Figure 1. CSCAP wholecity STEMI care network construction. 7 8 Figure 2. Geographic distribution of CSCAP. 9 10 11 Figure 3. CSCAP STEMI care flow chart. 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 25, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 29 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 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 CSCAP whole-city STEMI care network construction. 27 28 102x62mm (300 x 300 DPI) 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39 Geographic distribution of CSCAP

40 on September 25, 2021 by guest. Protected copyright. 170x170mm (300 x 300 DPI) 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 Page 33 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 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 31

32 http://bmjopen.bmj.com/ 33 34 35 CSCAP STEMI care flow chart. 36 148x130mm (300 x 300 DPI) 37 38 39

40 on September 25, 2021 by guest. Protected copyright. 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 34 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 Appendix table 1 Complete list of PCI hospitals participating in CSCAP-1 and CSCAP-2 3 Hospital Province/Municipality/ 4 Chizhou people's hospital Anhui 5 Taihe County People's Hospital Anhui 6 Anhui Provincial Hospital Anhui 7 8 Maanshan Central Hospital Anhui 9 Beijing Anzhen Hospital# Beijing 10 Beijing Chao-Yang Hospital# Beijing 11 Chinese PLA General Hospital丨Medical School of Chinese PLA* Beijing 12 General Hospital of Armed Police Forces* Beijing 13 General Hospital of Beijing Military Command of PLA* Beijing 14 Navy General Hospital Beijing 15 16 Peking University FirstFor Hospital# peer review only Beijing 17 Peking University People's Hospital# Beijing 18 Peking University Shougang Hospital# Beijing 19 Peking University Third Hospital# Beijing 20 The 306th Hospital of PLA Beijing 21 The 309th Hospital of Chinese People's Liberation Army Beijing 22 Daping Hospital,Research Institute of Surgery Third Military MedicalChongqing University 23 24 Southwest Hospital Chongqing 25 Xinqiao Hospital,Research Institute of Surgery Third Military MedicalChongqing University 26 Fuzhou General Hospital of Nanjing Military Command Fujian 27 Jiuquan people's Hospital of Gansu Province Gansu 28 Lanzhou General Hospital of Lanzhou Military Command Gansu 29 The First Hospital of Lanzhou University* Gansu 30 31 The First Hospital of Tianshui Gansu Dongguan Kanghua Hospital Guangdong 32 http://bmjopen.bmj.com/ 33 The Third People's Hospital of Dongguan Guangdong 34 The First People's Hospital of Shunde Guangdong 35 First Affiliated Hospital of Sun Yat-sen University# Guangdong 36 General Hospital of Guangzhou Military Command of PLA Guangdong 37 Guangdong General Hospital of Armed Police Force Guangdong 38 39 Guangdong General Hospital* Guangdong

40 Guangzhou Red Cross Hospital# Guangdong on September 25, 2021 by guest. Protected copyright. 41 Nanfang Hospital Guangdong 42 Wuhan General Hospital of Guangzhou Military Command Guangdong 43 Maoming Hospital of TCM Guangdong 44 Maoming People's Hospital Guangdong 45 Qingyuan people's Hospital Guangdong 46 47 Shantou Central Hospital Guangdong 48 The First Affiliated Hospital of Shantou University Medical CollegeGuangdong 49 Yuebei People's Hospital Guangdong 50 Shenzhen People's Hospital Guangdong 51 Sun yat-sen Cardiovascular Hospital of Shenzhen* Guangdong 52 The Fourth People's Hospital of Shenzhen Guangdong 53 54 Affiliated Hospital of Guangdong Medical University Guangdong 55 Danzhou People's Hospital Hainan 56 Haikou people's Hospital Hainan 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 Hainan General Hospital Hainan 3 Hainan Provincial Nong Ken Hospital Hainan 4 The First Affiliated Hospital of Hainan Medical University Hainan 5 Hainan Branch of PLA General Hospital Hainan 6 Hainan Third People's Hospital Hainan 7 8 Sanya People's Hospital Hainan 9 Affiliated Hospital of Hebei University Hebei 10 Baoding Second Central Hospital Hebei 11 the First Central Hospital of Baoding City Hebei 12 Cangzhou Central Hospital* Hebei 13 General Hospital of North China Petroleum Administration Bureau Hebei 14 Affiliated Hospital of Chengde Medical College Hebei 15 16 Chengde Central HospitalFor peer review onlyHebei 17 Handan Central Hospital Hebei 18 Handan First Hospital Hebei 19 Harrison international Heping Hospital Hebei 20 Hengshui Cardiovascular Hospital Hebei 21 Langfang Fourth People's Hospital Hebei 22 Qinhuangdao First Hospital Hebei 23 24 Bethune International Peace Hospital Hebei 25 Hebei General Hospital Hebei 26 The Second Hospital of Hebei Medical University* Hebei 27 Kailuan General Hospital Hebei 28 Tangshan Gongren Hospital* Hebei 29 Xingtai People's Hospital Hebei 30 31 Xingtai Third Hospital Hebei The Second Affiliated Hospital of Hebei North University Hebei 32 http://bmjopen.bmj.com/ 33 Zhangjiakou First Hospital Hebei 34 Zunhua people's Hospital Hebei 35 The Fourth Hospital of Harbin Medical University* Heilongjiang 36 The Second Affiliated Hospital of Harbin Medical University* Heilongjiang 37 Daqing Oilfield General Hospital* Heilongjiang 38 39 Longnan hospital in Daqing Heilongjiang

40 Greater Khingan Mountains Aera People’s Hospital Heilongjiang on September 25, 2021 by guest. Protected copyright. 41 Harbin First Hospital Heilongjiang 42 The Central Hospital of Jiamusi City Heilongjiang 43 Mudanjiang Cardiovascular Hospital Heilongjiang 44 Mudanjiang City 2rd People’s Hospital Heilongjiang 45 The 3rd Affiliated Hospital of Qiqihar Medical University Heilongjiang 46 47 Tsitsihar First Hospital Heilongjiang 48 Shuangyashan Coal General Hospital Heilongjiang 49 The First Affiliated Hospital of Harbin Medical University# Helongjiang 50 Anyang District Hospital Henan 51 The People's Hospital of Hebi Henan 52 Huaihe Hospital of Henan University Henan 53 54 Kaifeng Central Hospital Henan 55 Luohe Central Hospital Henan 56 The First Affiliated Hospital of Henan University of Science and Technology*Henan 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 The Second Affiliated Hospital of Henan University of Science and TechnologyHenan 3 Nanyang Central Hospital Henan 4 the Second People's Hospital of Pingdingshan Henan 5 Puyang Oilfield General Hospital Henan 6 Puyang People's Hospital Henan 7 8 First people's hospital of Shangqiu Henan 9 Xinxiang Central Hospital Henan 10 Xuchang Central Hospital Henan 11 First Affiliated Hospital of Henan University of TCM Henan 12 Henan Province People's Hospital* Henan 13 Henan Provincial Chest Hospital Henan 14 The 7th people's hospital of Zhengzhou Henan 15 16 The First AffiliatedFor Hospital ofpeer Zhengzhou University*review only Henan 17 Zhengzhou first people's hospital Henan 18 Zhumadian Central Hospital Henan 19 Alxa League Central Hospital Inner Mongolia 20 Baotou Central Hospital* Inner Mongolia 21 The First Affiliated Hospital of Baotou Medical College Inner Mongolia 22 Bayannur Hospital Inner Mongolia 23 24 Chifeng Municipal Hospital Inner Mongolia 25 The Affiliated Hospital of Chifeng University Inner Mongolia 26 Inner Mongolia People's Hospital Inner Mongolia 27 The Affiliated Hospital of Inner Mongolia Medical University Inner Mongolia 28 Ordos Central Hosiptal Inner Mongolia 29 Tong Liao City Hospital Inner Mongolia 30 31 Ulanqab Central Hospital Inner Mongolia People’s Hospital Wuhai City Inner Mongolia 32 http://bmjopen.bmj.com/ 33 Xilingol League Hospital Inner Mongolia 34 Inner Mongolia Xing'an Meng People's Hospital Inner Mongolia 35 Inner Mongolia Forestry General Hospital Inner Mongolia 36 Ansteel Group Hospital Liaoning 37 Dalian Municipal Central Hospital* Liaoning 38 39 The First Affiliated Hospital of Dalian Medical University* Liaoning

40 The Second Hospital of Dalian Medical University Liaoning on September 25, 2021 by guest. Protected copyright. 41 Dandong Central Hospital Liaoning 42 General Hospital Under The Fushun Mining Affairs Bureau Liaoning 43 Fuxin Central Hospital Liaoning 44 Huludao Central Hospital Liaoning 45 Jinzhou Central Hospital Liaoning 46 47 The First Affiliated Hospital of Liaoning Medical University* Liaoning 48 Shengjing Hospital of China Medicine University# Liaoning 49 The First Affiliated Hospital of Liaoning University of Traditional ChineseLiaoning Medicine /The First Clinical College / Liaoning Hospital of TCM 50 The First Hospital of China Medical University Liaoning 51 The First Hospital of China Medical University Liaoning 52 The Fourth Hospital of China Medical University* Liaoning 53 54 The General Hospital of Shenyang Military Liaoning 55 The People's Hospital of Liaoning Province* Liaoning 56 The Second Affiliated Hospital of Shenyang Medical College Liaoning 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 44 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 Tieling Central Hospital Liaoning 3 Yingkou Central Hospital Liaoning 4 Nanjing General Hospital Nanjing 5 Dezhou People's Hospital Shandong 6 Dongying People's Hospital Shandong 7 8 Jinan Central Hospital Shandong 9 Qianfo Hill Hospital Shandong 10 Qilu Hospital of Shandong University* Shandong 11 Shandong Provincial Hospital* Shandong 12 The No.4 Hospital 1946 Jinan Shandong Shandong 13 The Second Hospital of Shandong University Shandong 14 Jining NO.1 People's Hospital Shandong 15 16 The Affiliated HospitalFor of Jining peer Medical University* review only Shandong 17 Liaocheng People's Hospital* Shandong 18 The second People's Hospital Of Liaocheng Shandong 19 Linyi People's Hospital Shandong 20 Qingdao Central Hospital Shandong 21 Qingdao Municipal Hospital Shandong 22 The Affiliated Hospital of Qingdao University* Shandong 23 24 Taian City Central Hospital Shandong 25 The Affiliated Hospital of Taishan Medical University Shandong 26 Tengzhou Central People's Hospital Shandong 27 Anqiu City People's Hospital Shandong 28 The Affiliated Hospital of Weifang Medical University Shandong 29 Weifang People's Hospital Shandong 30 31 Weifang Traditional Chinese Hospital Shandong Changhai Hospital Shanghai 32 http://bmjopen.bmj.com/ 33 Jinshan Hospital of Fudan University Shanghai 34 NO.3 People's Hospital Affiliated to Shanghai Jiao Tong University ShanghaiSchool of Medicine 35 Renji Hospital Affiliated to Shanghai Jiao Tong University School ofShanghai Medicine 36 Ruijin Hospital, Shanghai Jiaotong University Shanghai 37 Shanghai Changzheng Hospital Shanghai 38 39 Shanghai Chest Hospital Shanghai

40 Shanghai East Hospital Shanghai on September 25, 2021 by guest. Protected copyright. 41 Shanghai Fengxian Central Hospital Shanghai 42 Shanghai General Hospital Shanghai 43 Shanghai Gongli Hospital Shanghai 44 Shanghai Jiading District Central Hospital Shanghai 45 Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai 46 47 Shanghai Minhang Central Hospital Shanghai 48 Shanghai ninth People's Hospital Affiliated to Shanghai Jiaotong UniversityShanghai 49 Shanghai Pudong New Area People's Hospital Shanghai 50 Shanghai Pudong New District Zhoupu Hospital Shanghai 51 Shanghai Putuo District Central Hospital Shanghai 52 The Fifth People's Affiliated Hospital of Fudan University Shanghai 53 54 The Huashan Hospital of Fudan University Shanghai 55 The Tenth People's Hospital of Tongji University* Shanghai 56 Tong Ren Hospital, Shanghai Jiao Tong University School of MedicineShanghai 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 44 BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 Tongji Hospital Shanghai 3 Xin Hua Hospital Affiliated to Shanghai Jiao Tong University SchoolShanghai of Medicine* 4 Zhongshan Hospital* Shanghai 5 General hospital of shanxi lu 'an mining (group) co., LTD Shanxi 6 Shanxi Luan Mining (Group) Co., Ltd. General Hospital Shanxi 7 8 With the Coal Group General Hospital* Shanxi 9 Shanxi Fenyang Hospital Shanxi 10 Shanxi Province Cardiovascular Disease Hospital* Shanxi 11 Taiyuan Center Hospital Shanxi 12 Taiyuan People’s Hospital# Shanxi 13 Tangdu Hospital, The Fourth Military Medical University Shanxi 14 Xijing Hospital, The Fourth Military Medical University Shanxi 15 16 The First People's HospitalFor of peerYangquan review only Shanxi 17 The First People's Hospital of JinZhong Shanxi 18 General Hospital of Chengdu Military Command of PLA Sichuan 19 Affiliated Hospital of Chinese People's Armed Police Force LogisticsTianjin Institute 20 TEDA International Cardiovascular Hospital* Tianjin 21 The 254th Hospital of Chinese People's Liberation Army Tianjin 22 The 254th Hospital of PLA Tianjin 23 24 The Affiliated Hospital of Armed Police Medical College# Tianjin 25 The Second Hospital of Tianjin Medical University* Tianjin 26 Tianjin Baodi District People's Hospital Tianjin 27 Tianjin Beichen Hospital Tianjin 28 Tianjin Chest Hospital* Tianjin 29 Tianjin Fifth Central Hospital Tianjin 30 31 Tianjin First Central Hospital Tianjin Tianjin Fourth Central Hospital Tianjin 32 http://bmjopen.bmj.com/ 33 Tianjin Jinghai hospital Tianjin 34 Tianjin Jixain People's Hospital Tianjin 35 Tianjin Medical University General Hospital* Tianjin 36 Tianjin People's Hospital* Tianjin 37 Tianjin Third Central Hospital Tianjin 38 39 Tianjin Xiqing Hospital Tianjin

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Protocol of the China STEMI Care Project (CSCAP): a 10- year project to improve quality of care by building up a regional STEMI care network ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-026362.R1

Article Type: Protocol

Date Submitted by the 31-Jan-2019 Author:

department of cardiology http://bmjopen.bmj.com/ Zhang, Zheng; The First Hospital of Lanzhou University, department of cardiology Chen, Yu-guo; Qilu Hospital of Shandong University, Department of Emergency Fu, Xianghua; The Second Hospital of Hebei Medical University, Department of Cardiology Gao, Chuanyu; Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Cardiology Li, Bao; Shanxi Cardiovascular Hospital, department of cardiology on September 25, 2021 by guest. Protected copyright. Chen, Ji-yan; Guangdong Cardiovascular Institute, Guangdong provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Cardiology Wu, Ming; Hainan General Hospital, Department of cardiology Ma, Yitong; The First Affiliated Hospital of Xinjiang Medical University, department of cardiology Zhao, Xingsheng; Inner Mongolia People’s Hospital, department of cardiology Chen, Yundai; Chinese PLA General Hospital, department of cardiology Yan, Hongbing; Fuwai Hospital, Chinese Academy of Medical Sciences, department of cardiology Xiang, Dingcheng; Guangzhou General Hospital of Guangzhou Military Region, Department of Cardiology Fang, Weiyi; Shanghai Chest Hospital, department of cardiology Mehta, Sameer; Lumen Foundation Naber, Christoph K; Stent Save a Life Ge, Junbo; Zhongshan Hospital Fudan University, department of cardiology

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 30 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 Huo, Yong ; Peking University First Hospital, 4 5 Primary Subject Evidence based practice 6 Heading: 7 8 Secondary Subject Heading: Medical management 9 Accreditation, chest pain center, network, reperfusion, ST-elevation Keywords: 10 myocardial infarction 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

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4 Protocol of the China STEMI Care Project (CSCAP): a 10-year project to BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 improve quality of care by building up a regional STEMI care network 8 9 10 11 12 Yan Zhang1, Bo Yu2, Yaling Han3, Jianan Wang4, Lixia Yang5, Zheng Wan6, Zheng 13 14 Zhang7, Yuguo Chen8, Xianghua Fu9, Chuanyu Gao10, Bao Li11, Jiyan Chen12, Ming 15 16 17 Wu13, Yitong Ma14, Xingsheng Zhao15, Yundai Chen16, Hongbing Yan17, Dingcheng 18 For peer review only 19 18 19 20 21 22 20 Xiang , Weiyi Fang , Sameer Mehta , Christoph K. Naber , Junbo Ge , *Yong 21 22 Huo1, on behalf of China STEMI Care Project (CSCAP) Investigators 23 24 25 26 27 1. Department of Cardiology, Peking University First Hospital, Beijing, China 28 29 30 2. Department of Cardiology, The Second Affiliated Hospital of Harbin Medical 31 32 33 University, Harbin, Heilongjiang Province, China 34 35 3. Department of Cardiology, The General Hospital of Shenyang Military Region,

36 http://bmjopen.bmj.com/ 37 38 Shenyang, Liaoning Province, China 39 40 4. Department of Cardiology, The Second Affiliated Hospital Zhejiang University 41 42 43 School of Medicine, Hangzhou, Zhejiang Province, China

44 on September 25, 2021 by guest. Protected copyright. 45 46 5. Department of Cardiology, Kunming General Hospital of Chengdu Military 47 48 Region, Kunming, Yunnan Department of Cardiology, China 49 50 51 6. Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, 52 53 China 54 55 56 7. Department of Cardiology, The First Hospital of Lanzhou University, Lanzhou, 57 58 59 Gansu Province, China 60 1

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4 8. Department of Emergency, Qilu Hospital of Shandong University, Jinan, BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Shandong Province, China 8 9 9. Department of Cardiology, The Second Hospital of Hebei Medical University, 10 11 12 Shijiazhuang, Hebei Province, China 13 14 10. Department of Cardiology, Henan Provincial People’s Hospital, Zhengzhou, 15 16 17 Henan Province, China 18 For peer review only 19 20 11. Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi 21 22 Province, China 23 24 25 12. Department of Cardiology, Guangdong General Hospital, Guangzhou, 26 27 Guangdong Province, China 28 29 30 13. Department of Cardiology, Hainan General Hospital, Haikou, Hainan Province, 31 32 33 China 34 35 14. Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical

36 http://bmjopen.bmj.com/ 37 38 University, Urumchi, The Xinjiang Uygur Autonomous Region, China 39 40 15. Department of Cardiology, Inner Mongolia People’s Hospital, Hohhot, The Inner 41 42 43 Mongolia Autonomous Region, China

44 on September 25, 2021 by guest. Protected copyright. 45 46 16. Department of Cardiology, Chinese PLA General Hospital, Beijing, China 47 48 17. Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical 49 50 51 Sciences, Beijing, China 52 53 18. Department of Cardiology, Guangzhou General Hospital of Guangzhou Military 54 55 56 Region, Guangzhou, Guangdong Province, China 57 58 59 19. Department of Cardiology, Shanghai Chest Hospital, Shanghai, China 60 2

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4 20. Lumen Foundation, Miami, USA BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 21. Stent - Save A Life!, Paris, France 8 9 22. Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 10 11 12 China 13 14 15 16 17 Running title: Protocol of China STEMI Care Project 18 For peer review only 19 20 21 22 Corresponding author: Yong Huo, MD 23 24 25 Department of Cardiology, Peking University First Hospital 26 27 8 Xishiku St, Xicheng District, Beijing 100034, China 28 29 30 Email: [email protected] 31 32 33 Phone: 86-10-83572283 34 35 Fax: 86-10-66137748

36 http://bmjopen.bmj.com/ 37 38 39 40 Date: 41 42 43 This study was initiated in 2011 and will be completed in 2021. Phase 1 (CSCAP-1) is

44 on September 25, 2021 by guest. Protected copyright. 45 46 conducted from 2011 to 2013, Phase 2 (CSCAP-2) is conducted from 2015 to 2018, 47 48 and Phase 3 (CSCAP-3) is conducted from 2018 to 2021, respectively. 49 50 51 52 53 54 55 56 57 58 59 60 3

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4 Abstract BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Introduction: Successful ST-segment elevation myocardial infarction (STEMI) 8 9 management is time-sensitive and is based on prompt reperfusion mainly to reduce 10 11 12 patient mortality. It has evolved from a single hospital care to an integrated regional 13 14 network approach over the last decades. This prospective study, named the China 15 16 17 STEMI Care Project (CSCAP), aims to show how implementation of different types 18 For peer review only 19 20 of integrated regional STEMI care networks can improve the reperfusion treatment 21 22 rate, shorten the total duration of myocardial ischemia, and lead to mortality reduction 23 24 25 step by step. 26 27 Methods and analysis: The CSCAP is a prospective, multicenter registry involving 3 28 29 30 phases. A total of 18 provinces, 4 municipalities and 2 autonomous regions in China 31 32 33 were included. Patients who met with the third universal definition of myocardial 34 35 infarction and the Chinese STEMI diagnosis and treatment guidelines were enrolled.

36 http://bmjopen.bmj.com/ 37 38 Phase 1 (CSCAP-1) focused on the in-hospital process optimization of primary 39 40 percutaneous coronary intervention (PPCI) hospitals, phase 2 (CSCAP-2) focused on 41 42 43 the PPCI hospital-based regional STEMI carenetwork construction together with

44 on September 25, 2021 by guest. Protected copyright. 45 46 emergency medical services and adjacent non-PPCI hospitals, and phase 3 (CSCAP-3) 47 48 focused on the whole-city STEMI care network construction by promoting chest pain 49 50 51 center accreditation. Systematic data collection, key performance index assessment 52 53 and subsequent improvement were implemented throughout the project to 54 55 56 continuously improve the quality of STEMI care. 57 58 59 Ethics and dissemination: The study has been reviewed and approved by the Ethics 60 4

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4 Committee of Peking University First Hospital. Ranking reports of quality of care will BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 be generated available to all participant affiliations. Results will be disseminated via 8 9 peer-reviewed scientific journals and presentations at congresses. 10 11 12 Trial registration number: NCT03821012 13 14 15 16 17 Strengths and limitations of this study 18 For peer review only 19 20  CSCAP is the first project focused on establishing an integrated regional STEMI 21 22 care network in China through in-hospital process optimization, PPCI 23 24 25 hospital-based regional STEMI care network construction and whole-city STEMI 26 27 care network construction step by step, which will help to understand the 28 29 30 situations extensively and then improve accordingly. 31 32 33  Evaluation, feedback and improvement system will be established, aiming to 34 35 provide a tailored and continuous quality of care improvement plan based on the

36 http://bmjopen.bmj.com/ 37 38 conditions of different regions to further integrate the STEMI care network 39 40 nationwide. 41 42 43  Hospitals are not randomly selected in CSCAP which might be lead to the lack of

44 on September 25, 2021 by guest. Protected copyright. 45 46 representatives to some degree. However, these hospitals are at a high level in 47 48 their region which is suitable to be core centers for regional network construction. 49 50 51 Their experiences could be valuable for hospitals in the same region but outside 52 53 this study. 54 55 56 57 58 59 60 5

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4 Introduction BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 The burden of cardiovascular diseases is increasing and posing a major public health 8 9 issue worldwide. The number of new onset of myocardial infarction will be 10 11 12 tremendous in China in the next 15 years with the increasing risk factors and aging 13 14 population [1]. The Chinese cardiovascular report in 2017 showed an increase in both 15 16 17 the percentage of hospitalization and mortality of acute myocardial infarction (AMI) 18 For peer review only 19 20 over the years. The trends of fast growth nationwide as well as higher in rural areas in 21 22 AMI mortality were observed since 2005 and 2013, respectively [2]. 23 24 25 ST-elevation myocardial infarction (STEMI), mainly caused by a sudden 26 27 obstruction of the coronary artery with thrombus, benefits from both increasing 28 29 30 reperfusion rate and shortening of the duration from the symptom occurrence to the 31 32 33 opening of the target vessel [3 4]. Although implementing an evidence-based 34 35 medicine significantly improves the prognosis of patients with STEMI, the gap of the

36 http://bmjopen.bmj.com/ 37 38 translational application is still large in real-world settings [5]. A majority of Chinese 39 40 STEMI patients miss the optimal treatment timing due to restrictions from both 41 42 43 patients and medical services [6 7]. Additionally, the ratio of significant deficiency in

44 on September 25, 2021 by guest. Protected copyright. 45 46 STEMI reperfusion treatment remained at the level of around 55% in the last decade. 47 48 Hence, the in-hospital mortality has not changed significantly yet [7]. 49 50 51 Successful treatment of STEMI is a systemic issue, and the solution is neither a 52 53 novel thrombolytic drug nor an intervention device. It can be brought about by 54 55 56 comprehensive factors, including patient health awareness, physician level, 57 58 59 physician–patient relationship, medical reimbursement system, prehospital emergency 60 6

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4 system, in-hospital treatment, connection mechanism between prehospital and BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 in-hospital care, and posthospital management. Experiences from both the American 8 9 Lifeline program and the European Stent – Save a Life can be used for reference. The 10 11 12 quality of medical service can be significantly improved by establishing a regional 13 14 STEMI care network through close collaboration with different levels of hospitals and 15 16 17 the emergency medical system (EMS) [8 9]. 18 For peer review only 19 20 Although large-scale studies have been conducted in China, such as Clinical 21 22 Pathways for Acute Coronary Syndromes in China (CPACS) focusing on the ACS 23 24 25 clinical pathway, Cardiovascular Disease in China (CCC) focusing on the in-hospital 26 27 treatment of acute coronary syndrome (ACS), China Acute Myocardial Infarction 28 29 30 (CAMI) Registry focusing on the management of both STEMI and non-STEMI, and 31 32 33 China Patient-centered Evaluative Assessment of Cardiac Events Retrospective Study 34 35 of Acute Myocardial Infarction (China PEACE-Retrospective AMI Study), none of

36 http://bmjopen.bmj.com/ 37 38 them focused on establishing a regional STEMI care network [7 10-12]. Serial 39 40 documents issued by the National Health Commission of China provide favorable 41 42 43 government support and further emphasize the importance of administrative

44 on September 25, 2021 by guest. Protected copyright. 45 46 departments of health care at all levels in strengthening the construction of regional 47 48 emergency medical treatment system [13-15]. 49 50 51 China has gradually increased the input of medical expense in the last few decades. 52 53 However, there are several types of medical insurances with different reimbursement 54 55 56 rate in China. The impacts of medical insurance policy coverage as well as 57 58 59 geographical and humanistic factors on STEMI management need to be discussed. 60 7

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4 Objectives BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 The 10-year project, named as China STEMI Care Project (CSCAP), aims to show 8 9 how implementation of different types of integrated regional STEMI care networks 10 11 12 can improve the reperfusion treatment rate, shorten the total duration of myocardial 13 14 ischemia, and lead to mortality reduction step by step. It will also provide useful 15 16 17 information when building up a STEMI care network in other similar regions. In 18 For peer review only 19 20 details, CSCAP focuses on improving the awareness of health and emergency 21 22 treatment for STEMI patients, increasing the ratio of reperfusion treatment, shortening 23 24 25 the overall duration of myocardial ischemia, and implementing standard secondary 26 27 prevention to improve the long-term prognosis by establishing and optimizing 28 29 30 medical care evaluation, feedback and improvement system with data support. 31 32 33 34 35 Methods and analysis

36 http://bmjopen.bmj.com/ 37 38 Study design 39 40 CSCAP is a prospective multicenter registry containing 3 phases. Phase 1 of CSCAP 41 42 43 (CSCAP-1) focused on the in-hospital process optimization of primary percutaneous

44 on September 25, 2021 by guest. Protected copyright. 45 46 coronary intervention (PPCI) hospitals. Phase 2 of CSCAP (CSCAP-2) focused on the 47 48 PPCI hospital-based regional STEMI care network construction with their adjacent 49 50 51 non-PPCI hospitals and EMS. Phase 3 of CSCAP (CSCAP-3) focused on the 52 53 whole-city STEMI care network construction by promoting chest pain center (CPC) 54 55 56 accreditation (Fig. 1). Systematic data collection, assessment of quality of care and 57 58 59 subsequent improvement were implemented throughout this study to continuously 60 8

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4 improve the quality of care. BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Organizational framework 8 9 CSCAP was established by the Chinese Medical Doctor Association and supported by 10 11 12 the National Health Commission of China in 2011. After collaborating with the 13 14 European Stent – Save a Life in CSCAP-3, China became its member country in 2017. 15 16 17 The project office, executive committee and steering committee were set up for the 18 For peer review only 19 20 purpose of management, implementation and academic support. Data management 21 22 and statistical analyses were conducted by the School of Public Health of Peking 23 24 25 University. 26 27 Site selection 28 29 30 CSCAP included 18 provinces (Anhui, Fujian, Gansu, Guangdong, Guangxi, Hainan, 31 32 33 Hebei, Heilongjiang, Henan, Hubei, Jiangsu, Liaoning, Shandong, Shanxi, Shaanxi, 34 35 Sichuan, Yunnan, and Zhejiang), 4 municipalities (Beijing, Chongqing, Shanghai, and

36 http://bmjopen.bmj.com/ 37 38 Tianjin) and 2 autonomous regions (Inner Mongolia and Xinjiang) in China when 39 40 considering incidence of STEMI, logistic as well as economic issues (Fig. 2). 41 42 43 A total of 53 tertiary hospitals qualified for PPCI in 14 provinces, municipalities or

44 on September 25, 2021 by guest. Protected copyright. 45 46 autonomous regions of China were enrolled in CSCAP-1. The qualification of these 47 48 selected hospitals is based on the numbers of PCI cases and cardiovascular 49 50 51 interventionists extracted from the national PCI registry database. Moreover, all of 52 53 them are able to provide 24/7 PPCI service. These hospitals were selected because 54 55 56 they were at the top level in their city and potentially a hub for regional network 57 58 59 construction in CSCAP-2. A total of 244 PCI hospitals with adjunct non-PCI hospitals 60 9

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4 from 24 provinces, municipalities and autonomous regions were selected to build up BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 the regional STEMI care network in CSCAP-2. A total of 7 cities (Harbin, Hangzhou, 8 9 Nanning, Qingdao, Shenzhen, Suzhou, and Taiyuan) from 7 provinces with different 10 11 12 EMS types were selected to build up the whole-city STEMI care network in 13 14 CSCAP-3 (Fig. 2). 15 16 17 Patient enrollment 18 For peer review only 19 20 Patients who met with the third universal definition of myocardial infarction and the 21 22 Chinese STEMI diagnosis and treatment guidelines were enrolled [16 17]. STEMI 23 24 25 patients with late admission to hospitals were also considered for the purpose of 26 27 exploring optimal methods to shorten total ischemic time containing both patient 28 29 30 delay and system delay issues. All patients received routine clinical assessments and 31 32 33 treatments without any experimental intervention. The updated guideline-directed 34 35 management such as reperfusion, auxiliary device implementation, elective

36 http://bmjopen.bmj.com/ 37 38 revascularization, medications and therapeutic lifestyle change will be implemented 39 40 during the whole study period. 41 42 43 In CSCAP-1, a total of 4,191 hospitalized patients, with symptom onset within 12 h

44 on September 25, 2021 by guest. Protected copyright. 45 46 regardless of whether receiving reperfusion or symptom onset within 12–24 h of 47 48 needing PPCI, were enrolled consecutively in 2012. In CSCAP-2, a total of 20,799 49 50 51 patients with STEMI occurrence within 30 days regardless of reperfusion were 52 53 enrolled consecutively from PPCI hospitals 3 times at a 6-month interval from 2015 54 55 56 to 2017. In CSCAP-3, a total of 30 hospitalized STEMI patients with symptom onset 57 58 59 within 30 days will be enrolled consecutively from both PCI and non-PCI hospitals in 60 10

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4 the whole-city network every 3 months. Those patients who survived after hospital BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 discharge will be followed up for 1 year. 8 9 Regional network construction 10 11 12 An integrated regional network contains PCI hospitals, non-PCI hospitals and EMS. 13 14 There are 3 major types of EMS exist in China: (1) independent-type EMS, which has 15 16 17 its own ambulances; (2) command-type EMS, which does not have its own 18 For peer review only 19 20 ambulances and uses local hospital ambulances; and (3) affiliate-type EMS, which is 21 22 based in hospitals and uses its ambulances. On the basis of these comprehensive 23 24 25 situations, patients may not be transported to optimal hospitals to receive effective 26 27 treatment in the shortest period because of incomplete communication [18]. Thus, 28 29 30 prehospital information transmission should be considered accordingly for hospital 31 32 33 alert and rapid and accurate transfer. 34 35 Although PPCI is the most effective treatment for STEMI, it is difficult to be

36 http://bmjopen.bmj.com/ 37 38 implemented in most of the primary hospitals, as they are limited by medical 39 40 condition, geographic location and techniques. Early thrombolysis and/or transfer PCI 41 42 43 strategy are the priority in most of these hospitals. Therefore, rapid identification of

44 on September 25, 2021 by guest. Protected copyright. 45 46 STEMI and referral to a hospital with PPCI ability are extremely important 47 48 components in establishing a regional STEMI care network in China. 49 50 51 Optimizing the in-hospital green channel can significantly shorten the 52 53 door-to-balloon (D2B) time and door-to-needle (D2N) time while establishing a CPC 54 55 56 to integrate multiple resources is one of the most important methods [19 20]. 57 58 59 Traditional CPC focuses on the optimization and integration of the in-hospital sources 60 11

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4 aimed to shorten the process. The medical system and patient factors together BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 determine the delay in STEMI emergency treatment [21]. The concept of a modern 8 9 CPC expands to establish an effective regional network aiming to shorten the total 10 11 12 ischemia duration, thereby maximizing the advantage of reperfusion therapy. The 13 14 CPC independent accreditation in China was initiated in 2013 and 2 types 15 16 17 accreditation standards were developed according to PPCI ability [22 23]. 18 For peer review only 19 20 Procedures 21 22 The treatment process of the patients suffered STEMI was based on the STEMI 23 24 25 protocol in the Announcement of Improving Medical Emergency Treatment 26 27 Performance of Acute Cardiovascular and Cerebrovascular Diseases issued by the 28 29 30 National Health Commission of China in 2015 [15]. Briefly, this flow chart included 31 32 33 1 center (EMS), 2 types of hospitals (PCI and non-PCI), 3 types of transfer methods 34 35 [EMS transfer to hospital, bypass emergency department (ED) and inter-hospital

36 http://bmjopen.bmj.com/ 37 38 transfer], and 11 clinical pathways. Different clinical pathways were selected to 39 40 execute the optimal emergency treatment based on the visiting time, approaching 41 42 43 method and hospital ability (Fig. 3). In addition, the procedures should be launched

44 on September 25, 2021 by guest. Protected copyright. 45 46 without results of myocardial biomarkers according to typical ischemic symptoms and 47 48 electrocardiogram (ECG). 49 50 51 Data collection and management 52 53 Data of all treatment process were collected, including patient general information, 54 55 56 prehospital treatment, in-hospital management and follow-up management (Table 1). 57 58 59 Considering the real situation in ED, many time points could not be recorded 60 12

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4 manually on time which might lead to missing and inaccurate data. Mobile device app BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 could record these time variables through a simple click and complete the prehospital 8 9 ECG transmission. The technique of data auto-capture becomes 10 11 12 more and more popular at present and should resolve this issue. All of these methods 13 14 are considered gradually in this study. 15 16 17 Data were inputted into a self-built electronic database together with two existing 18 For peer review only 19 20 databases of both CPC accreditation and national PCI registry by trained clinical 21 22 research coordinators and clinicians in each hospital. The quality of the data was 23 24 25 monitored and suspicious contents with missing, outlier and logical errors were 26 27 reviewed mainly. When all problems are resolved, the database is then locked for 28 29 30 statistical analysis. 31 32 33 The describing method was used in CSCAP to mainly rank data quality and 34 35 medical quality. Continuous variables were described as mean (standard deviation) or

36 http://bmjopen.bmj.com/ 37 38 median (interquartile range), while categorical variables were described as a 39 40 percentage. The multivariate regression model was used to evaluate the factors related 41 42 43 to the assessment of medical quality. The Cox model was used to analyze the

44 on September 25, 2021 by guest. Protected copyright. 45 46 association between exposures and medical outcomes. A P value < 0.05 was defined 47 48 as a significant difference. All analyses were performed using R 49 50 51 (http://www.R-project.org). 52 53 Key performance index 54 55 56 The National Cardiovascular Data Registry (NCDR), established since 1997, has 57 58 59 become the basis for project implementation and quality evaluation as well as 60 13

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4 research center medical quality improvement in the United States. It has a positive BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 impact on clinical practice, medical payment, clinical research and government 8 9 decision-making [24 25]. The present study referred to the NCDR model to optimize 10 11 12 the STEMI quality of care and established an evaluation, feedback and improvement 13 14 system for primary key performance indexes (KPIs). For KPI selection, PPCI 15 16 17 hospitals focused on the improvement in the PPCI capacity and efficiency, non-PPCI 18 For peer review only 19 20 hospitals focused on the improvement in rapid diagnosis, thrombolysis and referral 21 22 capacity to PPCI hospitals, and EMS focused on the improvement in information 23 24 25 transmission to alert hospitals early for the purpose of rapid and accurate transfer. 26 27 A total of 13 primary KPIs were selected for medical quality evaluation based on 28 29 30 different roles of EMS and hospitals in STEMI management (Table 2). These KPIs 31 32 33 are different in each phase but have internal logic. Except reperfusion rate, method 34 35 and cardiovascular outcomes, different treatment delay indexes are selected in

36 http://bmjopen.bmj.com/ 37 38 different phases which will shift to others step by step according to the progress of 39 40 network construction. D2N and D2B time, defined as from in-hospital FMC to target 41 42 43 vessel open, were used to evaluate in-hospital delay in CSCAP-1. First medical

44 on September 25, 2021 by guest. Protected copyright. 45 46 contact-to-balloon time (FMC2B) and first medical contact-to-needle time (FMC2N) 47 48 time, defined as FMC by emergency system or hospital to target vessel open, were 49 50 51 used to evaluate the whole medical system delay in CSCAP-2. Total ischemic time, 52 53 defined as from symptom onset to target vessel open, is used in CSCAP-3 to add the 54 55 56 information of patient delay. 57 58 59 The circular enrollment–evaluation–feedback-improvement method will be 60 14

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4 implemented in both CSCAP-2 and CSCAP-3. The quality feedback report contains BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 each KPI of the affiliation and its ranking within its regional network and among all 8 9 affiliations. Comparison of KPIs with itself and those of others was analyzed for 10 11 12 tailed improvements. 13 14 15 16 Patient and public involvement 17 18 The developmentFor of the peerresearch questions review and outcome only measures was informed by 19 20 21 the current situations of lacking of the integrated regional STEMI care network in 22 23 24 China. Patients were not offered the opportunity to participate in the study design. 25 26 They will obtain the information related to the study via public media as well as 27 28 29 academic publications. 30 31 32 33 34 Ethics and dissemination 35

36 http://bmjopen.bmj.com/ 37 The study was conducted in accordance with Declaration of Helsinki. The study 38 39 protocol was approved by the Ethics Committee of Peking University First Hospital. 40 41 42 Ranking reports of quality of care will be made available to all participant affiliations. 43

44 Results will be disseminated at international conferences and published in on September 25, 2021 by guest. Protected copyright. 45 46 47 peer-reviewed scientific journals or public media. 48 49 50 51 Discussion 52 53 The integration and optimization of an integrated regional network with government 54 55 56 support are urgent issues of STEMI care especially in China. CSCAP is the first 57 58 59 prospective registry study focused on regional network construction and will help 60 15

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4 extensively understand the basic situations and the differences with other countries, BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 which leading to optimized clinical practice and problem-guided improvement. It will 8 9 provide important information for the network construction shifting from the PPCI 10 11 12 hospital-centered regional network to the whole-city network step by step so as to 13 14 create an optimal integrate STEMI care system in China. 15 16 17 18 For peer review only 19 20 Contributions Yan Zhang coordinated the study, assisted with data collection, 21 22 performed data analysis, and drafted the manuscript. Bo Yu, Yaling Han, Jianan 23 24 25 Wang, Lixia Yang, Zheng Wan, Zheng Zhang, Yuguo Chen, Xianghua Fu, Chuanyu 26 27 Gao, Bao Li, Jiyan Chen, Ming Wu, Yitong Ma, Xingsheng Zhao, Yundai Chen, 28 29 30 Hongbing Yan, Dingcheng Xiang, Weiyi Fang, and Junbo Ge carried out the data 31 32 33 collection and helped draft the manuscript. Sameer Mehta and Christoph K Naber 34 35 participated in the design and helped draft the manuscript. Yong Huo, principal

36 http://bmjopen.bmj.com/ 37 38 investigator of the project, conceived and designed the project, helped collect data and 39 40 draft the manuscript. All authors reviewed the results and approved the final version 41 42 43 of the manuscript.

44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 Acknowledgments 49 50 51 The authors thank the study team members and patient advisers of all 52 53 collaborative hospitals and emergency medical services. They are also grateful to the 54 55 56 organizational coordination of Chinese Medical Doctor Association and China 57 58 59 Cardiovascular Association. They acknowledge the supports provided by the National 60 16

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4 Health Commission and local governments in China. BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 8 9 Funding CSCAP was funded by Sanofi-Aventis, Abbott, and AstraZeneca. 10 11 12 Competing interest None declared. 13 14 Patient consent for publication Not required. 15 16 17 Ethics approval This study was reviewed and approved by the Ethics Committees 18 For peer review only 19 20 at Peking University First Hospital. 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 17

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4 References BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 1. Stevens W, Peneva D, Li JZ, et al. Estimating the future burden of cardiovascular 8 9 disease and the value of lipid and blood pressure control therapies in China. 10 11 12 BMC health services research 2016;16:175. 13 14 2. Report on cardiovascular disease in China: Encyclopedia of China Publishing 15 16 17 house, 2017. 18 For peer review only 19 20 3. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the 21 22 management of ST-elevation myocardial infarction: a report of the American 23 24 25 College of Cardiology Foundation/American Heart Association Task Force on 26 27 Practice Guidelines. Circulation 2013;127:e362-425. 28 29 30 4. Task Force on the management of ST-segment elevation acute myocardial 31 32 33 infarction of the European Society of Cardiology (ESC), Steg PG, James SK, 34 35 et al. ESC Guidelines for the management of acute myocardial infarction in

36 http://bmjopen.bmj.com/ 37 38 patients presenting with ST-segment elevation. European heart journal 39 40 2012;33:2569-619. 41 42 43 5. Eagle KA, Nallamothu BK, Mehta RH, et al. Trends in acute reperfusion therapy

44 on September 25, 2021 by guest. Protected copyright. 45 46 for ST-segment elevation myocardial infarction from 1999 to 2006: we are 47 48 getting better but we have got a long way to go. European heart journal 49 50 51 2008;29:609-17. 52 53 6. Song L, Hu DY, Yan HB, et al. Influence of ambulance use on early reperfusion 54 55 56 therapies for acute myocardial infarction. Chinese medical journal 57 58 59 2008;121:771-5. 60 18

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4 7. Li J, Li X, Wang Q, et al. ST-segment elevation myocardial infarction in China BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 from 2001 to 2011 (the China PEACE-Retrospective Acute Myocardial 8 9 Infarction Study): a retrospective analysis of hospital data. Lancet 10 11 12 2015;385:441-51. 13 14 8. Jollis JG, Granger CB, Henry TD, et al. Systems of care for ST-segment-elevation 15 16 17 myocardial infarction: a report From the American Heart Association's 18 For peer review only 19 20 Mission: Lifeline. Circulation. Cardiovascular quality and outcomes 21 22 2012;5:423-8. 23 24 25 9. Kristensen SD, Fajadet J, Di Mario C, et al. Implementation of primary angioplasty 26 27 in Europe: stent for life initiative progress report. EuroIntervention : journal of 28 29 30 EuroPCR in collaboration with the Working Group on Interventional 31 32 33 Cardiology of the European Society of Cardiology 2012;8:35-42. 34 35 10. Gao R, Patel A, Gao W, et al. Prospective observational study of acute coronary

36 http://bmjopen.bmj.com/ 37 38 syndromes in China: practice patterns and outcomes. Heart 2008;94:554-60. 39 40 11. Hao Y, Liu J, Liu J, et al. Rationale and design of the Improving Care for 41 42 43 Cardiovascular Disease in China (CCC) project: A national effort to prompt

44 on September 25, 2021 by guest. Protected copyright. 45 46 quality enhancement for acute coronary syndrome. American heart journal 47 48 2016;179:107-15. 49 50 51 12. Xu H, Li W, Yang J, et al. The China Acute Myocardial Infarction (CAMI) 52 53 Registry: A national long-term registry-research-education integrated platform 54 55 56 for exploring acute myocardial infarction in China. American heart journal 57 58 59 2016;175:193-201.e3. 60 19

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4 13. Pre-hospital medical emergency management measures. Chinese Village Medicine BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 2014:85-86. (In Chinese) 8 9 14. National Health Commission of China. Guiding Principles for Construction and 10 11 12 Management of Chest Pain Center (Trial). 2017. (In Chinese) 13 14 15. National Health Commission of China. The Announcement of Improving Medical 15 16 17 Emergency Treatment Performance of Acute Cardiovascular and 18 For peer review only 19 20 Cerebrovascular Diseases. 2015. (In Chinese) 21 22 16. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial 23 24 25 infarction. Circulation 2012;126:2020-35. 26 27 17. Chinese Society of Cardiology, Editorial board of Chinese Journal of Cardiology. 28 29 30 Guidelines for the diagnosis and treatment of acute ST segment elevation 31 32 33 myocardial infarction. Chinese Journal of Cardiology 2015;43:380-93. (In 34 35 Chinese)

36 http://bmjopen.bmj.com/ 37 38 18. Ranasinghe I, Rong Y, Du X, et al. System barriers to the evidence-based care of 39 40 acute coronary syndrome patients in China: qualitative analysis. Circulation. 41 42 43 Cardiovascular quality and outcomes 2014;7:209-16.

44 on September 25, 2021 by guest. Protected copyright. 45 46 19. Bradley EH, Herrin J, Wang Y, et al. Strategies for reducing the door-to-balloon 47 48 time in acute myocardial infarction. The New England journal of medicine 49 50 51 2006;355:2308-20. 52 53 20. Graff LG, Dallara J, Ross MA, et al. Impact on the care of the emergency 54 55 56 department chest pain patient from the chest pain evaluation registry 57 58 59 (CHEPER) study. The American journal of cardiology 1997;80:563-8. 60 20

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4 21. Windecker S, Bax JJ, Myat A, et al. Future treatment strategies in ST-segment BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 elevation myocardial infarction. Lancet 2013;382:644-57. 8 9 22. China Chest Pain Center Accreditation Work Committee. Standard for Chinese 10 11 12 Chest Pain Center accreditation. Chinese Journal of Interventional Cardiology 13 14 2016;24:121-30. (In Chinese) 15 16 17 23. China Chest Pain Center Accreditation Work Committee. Standard for Chinese 18 For peer review only 19 20 Primary Chest Pain Center accreditation. Chinese Journal of Interventional 21 22 Cardiology 2016;24:131-33. (In Chinese) 23 24 25 24. Diercks DB, Kontos MC, Chen AY, et al. Utilization and impact of pre-hospital 26 27 electrocardiograms for patients with acute ST-segment elevation myocardial 28 29 30 infarction: data from the NCDR (National Cardiovascular Data Registry) 31 32 33 ACTION (Acute Coronary Treatment and Intervention Outcomes Network) 34 35 Registry. Journal of the American College of Cardiology 2009;53:161-6.

36 http://bmjopen.bmj.com/ 37 38 25. Krim SR, Vivo RP, Krim NR, et al. Regional differences in clinical profile, 39 40 quality of care, and outcomes among Hispanic patients hospitalized with acute 41 42 43 myocardial infarction in the Get with Guidelines-Coronary Artery Disease

44 on September 25, 2021 by guest. Protected copyright. 45 46 (GWTG-CAD) registry. American heart journal 2011;162:988-95. e4. 47 48 49 50 51 52 53 54 55 56 57 58 59 60 21

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4 Table 1. CSCAP data elements BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Category Example elements 8 9 Patient baseline information Demographics (age, sex, ethnicity, occupation, marriage 10 11 12 status, and medical insurance type) 13 14 15 Risk factors (smoking status, BMI, hypertension, diabetes, 16 17 dyslipidemia, peripheral artery disease, MI history, stroke 18 For peer review only 19 20 history, and prior revascularization) 21 22 Clinical presentation (blood pressure, heart rate, and cardiac 23 24 25 function classification) 26 27 28 Prehospital information Patient (symptoms, symptom onset time, and hospital 29 30 approaching method) 31 32 33 EMS (response time, transfer process, first ECG time, ECG 34 35 transmission ratio, and bypass ED ratio)

36 http://bmjopen.bmj.com/ 37 38 Non-PCI hospital (hospital approaching method, first medical 39 40 41 contact time, admission time, first ECG time, diagnosis time, 42 43 consent time, reperfusion and other treatment, DI-DO time,

44 on September 25, 2021 by guest. Protected copyright. 45 46 and transfer process) 47 48 PCI hospital information Reperfusion (methods, indication and contraindication, and 49 50 51 nonreperfusion reasons) 52 53 54 Treatment delay (hospital approaching method, first medical 55 56 contact time, bypass ED ratio, admission time, first ECG time, 57 58 59 catheter lab ready time, consent time, D2B, D2N, FMC2B, 60 22

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4 FMC2N, total ischemic time, and reasons of delay) BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 PCI procedures (operative route, coronary angiography 8 9 results, aspiration, culprit vessels, stent, and elective PCI) 10 11 12 Thrombolytic procedures (thrombolytic agent, dose, and 13 14 outcome) 15 16 17 Medications (loading dose DAPT and statin, antiplatelets, 18 For peer review only 19 20 β-blockers, statin, ACEI/ARB, GP IIb/IIIa inhibitor, and 21 22 anticoagulant with dose and contraindication information) 23 24 25 Laboratory results (troponin, CK-MB, creatinine, hemoglobin, 26 27 HbA1c, fasting glucose, BNP or NT-proBNP, lipid profiles, 28 29 30 ECG, and UCG) 31 32 33 Discharge (diagnosis, in-hospital duration, expense, and 34 35 medications)

36 http://bmjopen.bmj.com/ 37 38 Outcomes (death, non-fatal reinfarction, nonfatal stroke, 39 40 revascularization, mechanical complication, and bleeding) 41 42 43 Follow-up and management Presentation status (symptom, cardiac function classification,

44 on September 25, 2021 by guest. Protected copyright. 45 46 blood pressure, heart rate, and follow-up on-time ratio) 47 48 Laboratory results (lipid profiles, glucose traits, HbA1c, 49 50 51 creatinine, hemoglobin, BNP or NT-proBNP, ECG, and 52 53 UCG) 54 55 56 Medications (antiplatelets, β-blockers, statin, and ACEI/ARB) 57 58 59 Risk factor control rate (Blood pressure, lipid, glucose, and 60 23

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4 smoking cessation) BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Outcomes (death, nonfatal reinfarction, stroke, 8 9 revascularization, rehospitalization due to unstable angina 10 11 12 pectoris, heart failure or other cardiovascular reasons, and 13 14 bleeding) 15 16 17 ACEI, Angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; 18 For peer review only 19 20 BMI, body mass index; BNP, brain natriuretic peptide; CK-MB, creatine kinase MB 21 22 isoenzyme; DAPT, dual antiplatelet therapy; D2B, door to balloon; D2N, door to 23 24 25 needle; DI–DO, door in–door out; ECG, electrocardiograph; ED, emergency 26 27 department; EMS, emergency medical service; FMC2B, first medical contact to 28 29 30 balloon; FMC2N, first medical contact to needle injection; GP IIb/IIIa, glycoprotein 31 32 33 IIb/IIIa; HbA1c, glycosylated hemoglobin A1c; MI, myocardial infarction; 34 35 NT-ProBNP, N-terminal pro–brain natriuretic peptide; PCI, percutaneous coronary

36 http://bmjopen.bmj.com/ 37 38 intervention; UCG, ultrasound cardiogram. 39 40 41 42 43

44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 24

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4 Table 2. Primary performance measures for evaluating medical care quality BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Primary performance measures 8 9 Prehospital care 10 11 12 Symptom onset to arrival in hospital (min) 13 14 15 Hospital admission ratio via ambulance (%) 16 17 Prehospital ECG transmission ratio (%) 18 For peer review only 19 20 Bypass ED ratio in patients with symptom onset within 12 h (%) 21 22 Reperfusion 23 24 25 Overall reperfusion ratio (%) 26 27 28 Thrombolysis ratio in patients with symptom onset within 12 h (%) 29 30 Primary PCI ratio in patients with symptom onset within 12 h (%) 31 32 33 D2B in patients with symptom onset within 12 h (min) 34 35 D2N in patients with symptom onset within 12 h (min)

36 http://bmjopen.bmj.com/ 37 38 Discharge 39 40 41 Usage of both DAPT, statin, β blocker, and ACEI/ARB in patients without contraindication (%) 42 43 Outcomes

44 on September 25, 2021 by guest. Protected copyright. 45 46 In-hospital mortality (%) 47 48 Follow-up and management 49 50 51 1-Year on-time follow-up ratio (%) 52 53 54 1-Year MACE (%), including mortality, non-fatal myocardial infarction, non-fatal stroke, and 55 56 hospitalization due to heart failure or acute coronary syndrome 57 58 59 ACEI, Angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; 60 25

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4 DAPT, dual antiplatelet therapy; D2B, door to balloon; D2N, door to needle; ECG, BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 electrocardiogram; ED, emergency department; PCI, percutaneous coronary 8 9 intervention; MACE, major adverse cardiovascular event. 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

36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

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4 Figure legends BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Figure 1. CSCAP whole-city STEMI care network construction. 8 9 Figure 2. Geographic distribution of CSCAP. 10 11 12 Figure 3. CSCAP STEMI emergency care flow chart. 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

36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 27

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32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 25, 2021 by guest. Protected copyright. 170x170mm (300 x 300 DPI) 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 Page 31 of 30 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 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 31

32 http://bmjopen.bmj.com/ 33 34 35 36 170x148mm (300 x 300 DPI) 37 38 39

Protocol of the China ST-segment elevation myocardial infarction (STEMI) Care Project (CSCAP): a 10-year project to improve quality of care by building up a regional STEMI care network

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-026362.R2

Article Type: Protocol

Date Submitted by the 25-Mar-2019 Author:

Complete List of Authors: Zhang, Yan; Peking University First Hospital, Department of Cardiology Yu, Bo; Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, 2nd Affiliated Hospital of Harbin Medical University, Cardiology Han, YL; The General Hospital of Shenyang Military Region, Department of Cardiology Wang, Jianan; The Second Affiliated Hospital, Zhejiang University, Department of Cardiology Yang, Lixia; Kunming General Hospital of Chengdu Military Region, Department of Cardiology Wan, Zheng; The General Hospital of Tianjin Medical University, http://bmjopen.bmj.com/ department of cardiology Zhang, Zheng; The First Hospital of Lanzhou University, department of cardiology Chen, Yu-guo; Qilu Hospital of Shandong University, Department of Emergency Fu, Xianghua; The Second Hospital of Hebei Medical University, Department of Cardiology Gao, Chuanyu; Henan Provincial People’s Hospital, Zhengzhou University

People’s Hospital, Cardiology on September 25, 2021 by guest. Protected copyright. Li, Bao; Shanxi Cardiovascular Hospital, department of cardiology Chen, Ji-yan; Guangdong Cardiovascular Institute, Guangdong provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Cardiology Wu, Ming; Hainan General Hospital, Department of cardiology Ma, Yitong; The First Affiliated Hospital of Xinjiang Medical University, department of cardiology Zhao, Xingsheng; Inner Mongolia People’s Hospital, department of cardiology Chen, Yundai; Chinese PLA General Hospital, department of cardiology Yan, Hongbing; Fuwai Hospital, Chinese Academy of Medical Sciences, department of cardiology Xiang, Dingcheng; Guangzhou General Hospital of Guangzhou Military Region, Department of Cardiology Fang, Weiyi; Shanghai Chest Hospital, department of cardiology Mehta, Sameer; Lumen Foundation Naber, Christoph K; Stent Save a Life Ge, Junbo; Zhongshan Hospital Fudan University, department of

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 29 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 1 2 3 cardiology 4 Huo, Yong ; Peking University First Hospital, 5 6 Primary Subject Evidence based practice 7 Heading: 8 Secondary Subject Heading: Medical management 9 10 Accreditation, chest pain center, network, reperfusion, ST-elevation Keywords: 11 myocardial infarction 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

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4 Protocol of the China ST-segment elevation myocardial infarction (STEMI) Care BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Project (CSCAP): a 10-year project to improve quality of care by building up a 8 9 regional STEMI care network 10 11 12 13 14 Yan Zhang1, Bo Yu2, Yaling Han3, Jianan Wang4, Lixia Yang5, Zheng Wan6, Zheng 15 16 17 Zhang7, Yuguo Chen8, Xianghua Fu9, Chuanyu Gao10, Bao Li11, Jiyan Chen12, Ming 18 For peer review only 19 13 14 15 16 17 20 Wu , Yitong Ma , Xingsheng Zhao , Yundai Chen , Hongbing Yan , Dingcheng 21 22 Xiang18, Weiyi Fang19, Sameer Mehta20, Christoph K. Naber21, Junbo Ge22, *Yong 23 24 25 Huo1, on behalf of China STEMI Care Project (CSCAP) Investigators 26 27 28 29 30 1. Department of Cardiology, Peking University First Hospital, Beijing, China 31 32 33 2. Department of Cardiology, The Second Affiliated Hospital of Harbin Medical 34 35 University, Harbin, Heilongjiang Province, China

36 http://bmjopen.bmj.com/ 37 38 3. Department of Cardiology, The General Hospital of Shenyang Military Region, 39 40 Shenyang, Liaoning Province, China 41 42 43 4. Department of Cardiology, The Second Affiliated Hospital Zhejiang University

44 on September 25, 2021 by guest. Protected copyright. 45 46 School of Medicine, Hangzhou, Zhejiang Province, China 47 48 5. Department of Cardiology, Kunming General Hospital of Chengdu Military 49 50 51 Region, Kunming, Yunnan Department of Cardiology, China 52 53 6. Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, 54 55 56 China 57 58 59 7. Department of Cardiology, The First Hospital of Lanzhou University, Lanzhou, 60 1

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4 Gansu Province, China BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 8. Department of Emergency, Qilu Hospital of Shandong University, Jinan, 8 9 Shandong Province, China 10 11 12 9. Department of Cardiology, The Second Hospital of Hebei Medical University, 13 14 Shijiazhuang, Hebei Province, China 15 16 17 10. Department of Cardiology, Henan Provincial People’s Hospital, Zhengzhou, 18 For peer review only 19 20 Henan Province, China 21 22 11. Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi 23 24 25 Province, China 26 27 12. Department of Cardiology, Guangdong General Hospital, Guangzhou, 28 29 30 Guangdong Province, China 31 32 33 13. Department of Cardiology, Hainan General Hospital, Haikou, Hainan Province, 34 35 China

36 http://bmjopen.bmj.com/ 37 38 14. Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical 39 40 University, Urumchi, The Xinjiang Uygur Autonomous Region, China 41 42 43 15. Department of Cardiology, Inner Mongolia People’s Hospital, Hohhot, The Inner

44 on September 25, 2021 by guest. Protected copyright. 45 46 Mongolia Autonomous Region, China 47 48 16. Department of Cardiology, Chinese PLA General Hospital, Beijing, China 49 50 51 17. Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical 52 53 Sciences, Beijing, China 54 55 56 18. Department of Cardiology, Guangzhou General Hospital of Guangzhou Military 57 58 59 Region, Guangzhou, Guangdong Province, China 60 2

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4 19. Department of Cardiology, Shanghai Chest Hospital, Shanghai, China BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 20. Lumen Foundation, Miami, USA 8 9 21. Stent - Save A Life!, Paris, France 10 11 12 22. Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 13 14 China 15 16 17 18 For peer review only 19 20 Running title: Protocol of China STEMI Care Project 21 22 23 24 25 Corresponding author: Yong Huo, MD 26 27 Department of Cardiology, Peking University First Hospital 28 29 30 8 Xishiku St, Xicheng District, Beijing 100034, China 31 32 33 Email: [email protected] 34 35 Phone: 86-10-83572283

36 http://bmjopen.bmj.com/ 37 38 Fax: 86-10-66137748 39 40 41 42 43 Date:

44 on September 25, 2021 by guest. Protected copyright. 45 46 This study was initiated in 2011 and will be completed in 2021. Phase 1 (CSCAP-1) is 47 48 conducted from 2011 to 2013, Phase 2 (CSCAP-2) is conducted from 2015 to 2018, 49 50 51 and Phase 3 (CSCAP-3) is conducted from 2018 to 2021, respectively. 52 53 54 55 56 57 58 59 60 3

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4 Abstract BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Introduction: Successful ST-segment elevation myocardial infarction (STEMI) 8 9 management is time-sensitive and is based on prompt reperfusion mainly to reduce 10 11 12 patient mortality. It has evolved from a single hospital care to an integrated regional 13 14 network approach over the last decades. This prospective study, named the China 15 16 17 STEMI Care Project (CSCAP), aims to show how implementation of different types 18 For peer review only 19 20 of integrated regional STEMI care networks can improve the reperfusion treatment 21 22 rate, shorten the total duration of myocardial ischemia, and lead to mortality reduction 23 24 25 step by step. 26 27 Methods and analysis: The CSCAP is a prospective, multicenter registry study of 3 28 29 30 phases. A total of 18 provinces, 4 municipalities and 2 autonomous regions in China 31 32 33 were included. Patients who meet the third universal definition of myocardial 34 35 infarction and the Chinese STEMI diagnosis and treatment guidelines are enrolled.

36 http://bmjopen.bmj.com/ 37 38 Phase 1 (CSCAP-1) focuses on the in-hospital process optimization of primary 39 40 percutaneous coronary intervention (PPCI) hospitals, phase 2 (CSCAP-2) focuses on 41 42 43 the PPCI hospital-based regional STEMI care network construction together with

44 on September 25, 2021 by guest. Protected copyright. 45 46 emergency medical services and adjacent non-PPCI hospitals, while phase 3 47 48 (CSCAP-3) focuses on the whole-city STEMI care network construction by 49 50 51 promoting chest pain center accreditation. Systematic data collection, key 52 53 performance index assessment and subsequent improvement are implemented 54 55 56 throughout the project to continuously improve the quality of STEMI care. 57 58 59 Ethics and dissemination: The study has been reviewed and approved by the Ethics 60 4

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4 Committee of Peking University First Hospital. Ranking reports of quality of care will BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 be generated available to all participant affiliations. Results will be disseminated via 8 9 peer-reviewed scientific journals and presentations at congresses. 10 11 12 Trial registration number: NCT03821012 13 14 15 16 17 Strengths and limitations of this study 18 For peer review only 19 20  CSCAP is the first project focuses on establishing an integrated regional STEMI 21 22 care network in China through in-hospital process optimization, PPCI 23 24 25 hospital-based regional STEMI care network construction and whole-city STEMI 26 27 care network construction step by step, which will help us to understand the 28 29 30 situations extensively and then improve accordingly. 31 32 33  Evaluation, feedback and improvement system will be established, aiming to 34 35 provide a tailored and continuous quality of care improvement plan based on the

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4 Introduction BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 The burden of cardiovascular diseases is increasing and posing a major public health 8 9 issue worldwide. The number of new onset of myocardial infarction will be 10 11 12 tremendous in China in the next 15 years with the increasing risk factors and aging 13 14 population [1]. The Chinese cardiovascular report in 2017 has shown an increase in 15 16 17 both the percentage of hospitalization and mortality of acute myocardial infarction 18 For peer review only 19 20 (AMI) over the years. The trends of fast growth nationwide as well as higher AMI 21 22 mortality in rural areas in were observed since 2005 and 2013, respectively [2]. 23 24 25 ST-elevation myocardial infarction (STEMI), mainly caused by a sudden 26 27 obstruction of the coronary artery with thrombus, benefits from both increasing 28 29 30 reperfusion rate and shortening of the duration from the symptom occurrence to the 31 32 33 opening of the target vessel [3 4]. Although implementing an evidence-based 34 35 medicine significantly improves the prognosis of patients with STEMI, the gap of

36 http://bmjopen.bmj.com/ 37 38 clinical application is still large in real-world settings [5]. A majority of Chinese 39 40 STEMI patients miss the optimal treatment timing due to restrictions from both 41 42 43 patients and medical services [6 7]. Additionally, the ratio of STEMI reperfusion

44 on September 25, 2021 by guest. Protected copyright. 45 46 treatment remained at the level of around 55% in the last decade. Hence, the 47 48 in-hospital mortality has not changed significantly yet [7]. 49 50 51 Successful treatment of STEMI is a systemic issue, and the solution is neither a 52 53 novel thrombolytic drug nor an intervention device. It can be brought about by 54 55 56 comprehensive factors, including the patients’ health awareness, physician’s skill, 57 58 59 physician–patient’s relationship, medical reimbursement system, prehospital 60 6

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4 emergency medical system (EMS), in-hospital treatment, connection mechanism BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 between prehospital and in-hospital care, and posthospital management. Experiences 8 9 from both the American Lifeline program and the European Stent – Save a Life can 10 11 12 be used for reference. The quality of medical care can be significantly improved by 13 14 establishing a regional STEMI care network through close collaboration between 15 16 17 hospitals of different levels and EMS [8 9]. 18 For peer review only 19 20 Although large-scale studies have been conducted in China, such as Clinical 21 22 Pathways for Acute Coronary Syndromes in China (CPACS) focusing on the ACS 23 24 25 clinical pathway, Cardiovascular Disease in China (CCC) focusing on the in-hospital 26 27 treatment of acute coronary syndrome (ACS), China Acute Myocardial Infarction 28 29 30 (CAMI) Registry focusing on the management of both STEMI and non-STEMI, and 31 32 33 China Patient-centered Evaluative Assessment of Cardiac Events Retrospective Study 34 35 of Acute Myocardial Infarction (China PEACE-Retrospective AMI Study), none of

36 http://bmjopen.bmj.com/ 37 38 them focused on establishing a regional STEMI care network [7 10-12]. Serial 39 40 documents issued by the National Health Commission of China provide favorable 41 42 43 government supports and further emphasize the important rolls of administrative

44 on September 25, 2021 by guest. Protected copyright. 45 46 departments of health care at all levels in strengthening the construction of regional 47 48 emergency care network [13-15]. 49 50 51 China has gradually increased the input of medical expense in the last few decades. 52 53 However, there are several types of medical insurances with different reimbursement 54 55 56 policy in China. The impacts of health economic factors as well as geographical and 57 58 59 humanistic factors on quality of STEMI care need to be discussed either. 60 7

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36 http://bmjopen.bmj.com/ 37 38 Study design 39 40 CSCAP is a prospective multicenter registry containing 3 phases. Phase 1 of CSCAP 41 42 43 (CSCAP-1) focuses on the in-hospital process optimization of primary percutaneous

44 on September 25, 2021 by guest. Protected copyright. 45 46 coronary intervention (PPCI) hospitals. Phase 2 of CSCAP (CSCAP-2) focuses on the 47 48 PPCI hospital-based regional STEMI care network construction with their adjacent 49 50 51 non-PPCI hospitals and EMS. Phase 3 of CSCAP (CSCAP-3) focuses on the 52 53 whole-city STEMI care network construction by promoting chest pain center (CPC) 54 55 56 accreditation (Fig. 1). Systematic data collection, assessment of quality of care and 57 58 59 subsequent improvement are implemented throughout this study to continuously 60 8

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4 improve the quality of care. BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Organizational framework 8 9 CSCAP was established by the Chinese Medical Doctor Association and supported by 10 11 12 the National Health Commission of China in 2011. After collaborating with the 13 14 European Stent – Save a Life in CSCAP-3, China became its member country in 2017. 15 16 17 The project office, executive committee and steering committee were set up for the 18 For peer review only 19 20 purposes of management, implementation and academic support. Data management 21 22 and statistical analyses were conducted by the School of Public Health of Peking 23 24 25 University. 26 27 Site selection 28 29 30 CSCAP included 18 provinces (Anhui, Fujian, Gansu, Guangdong, Guangxi, Hainan, 31 32 33 Hebei, Heilongjiang, Henan, Hubei, Jiangsu, Liaoning, Shandong, Shanxi, Shaanxi?, 34 35 Sichuan, Yunnan, and Zhejiang), 4 municipalities (Beijing, Chongqing, Shanghai, and

36 http://bmjopen.bmj.com/ 37 38 Tianjin) and 2 autonomous regions (Inner Mongolia and Xinjiang) in China when 39 40 considering incidence of STEMI, logistic as well as economic issues. 41 42 43 A total of 53 tertiary hospitals qualified for PPCI in 10 provinces, 2 municipalities

44 on September 25, 2021 by guest. Protected copyright. 45 46 and 2 autonomous regions of China were enrolled in CSCAP-1. The qualification of 47 48 these selected hospitals was based on the numbers of PCI cases and cardiovascular 49 50 51 interventionists extracted from the national PCI registry database. Moreover, all of 52 53 them are able to provide 24/7 PPCI service. These hospitals were selected because 54 55 56 they were at the top level in their city and potentially a hub for regional network 57 58 59 construction in CSCAP-2. A total of 244 PCI hospitals with adjunct non-PCI hospitals 60 9

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4 from 18 provinces, 4 municipalities and 2 autonomous regions were selected to build BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 up the regional STEMI care network in CSCAP-2. A total of 7 cities (Harbin, 8 9 Hangzhou, Nanning, Qingdao, Shenzhen, Suzhou, and Taiyuan) from 6 provinces and 10 11 12 1 autonomous region with different EMS types were selected to build up the 13 14 whole-city STEMI care network in CSCAP-3. 15 16 17 Patient enrollment 18 For peer review only 19 20 Patients who met with the third universal definition of myocardial infarction and the 21 22 Chinese STEMI diagnosis and treatment guidelines were enrolled [16 17]. STEMI 23 24 25 patients with late admission to hospitals were also considered for the purpose of 26 27 exploring optimal methods to shorten total ischemic time causing by both patient and 28 29 30 system delay. All patients received routine clinical assessments and treatments 31 32 33 without any experimental intervention. The updated guideline-directed management 34 35 such as reperfusion, auxiliary device implementation, elective revascularization,

36 http://bmjopen.bmj.com/ 37 38 medications and therapeutic lifestyle change will be implemented during the whole 39 40 study period. 41 42 43 In CSCAP-1, a total of 4,191 hospitalized patients, with symptom onset within 12 h

44 on September 25, 2021 by guest. Protected copyright. 45 46 regardless of whether receiving reperfusion or symptom onset within 12–24 h but still 47 48 need PPCI, were enrolled consecutively in 2012. In CSCAP-2, a total of 20,799 49 50 51 patients with STEMI occurrence within 30 days regardless of reperfusion were 52 53 enrolled consecutively from PPCI hospitals 3 times at a 6-month interval from 2015 54 55 56 to 2017. In CSCAP-3, a total of 30 hospitalized STEMI patients with symptom onset 57 58 59 within 30 days will be enrolled consecutively from both PCI and non-PCI hospitals in 60 10

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4 the whole-city network every 3 months. Those patients who survived after hospital BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 discharge will be followed up for 1 year. 8 9 Regional network construction 10 11 12 An integrated regional network contains PCI hospitals, non-PCI hospitals and EMS. 13 14 There are 3 major types of EMS in China: (1) independent EMS, which has its own 15 16 17 ambulances; (2) commanding EMS, which does not have its own ambulances and 18 For peer review only 19 20 uses hospital ambulances; and (3) affiliated EMS, which is based in hospitals and uses 21 22 their ambulances. Due to these comprehensive situations, patients may not be 23 24 25 transported to optimal hospitals to receive effective treatment in the shortest period 26 27 because of incomplete communication [18]. Thus, prehospital information 28 29 30 transmission should be considered accordingly for hospital alert and rapid and 31 32 33 accurate transfer. 34 35 Although PPCI is the most effective treatment for STEMI, it is difficult to be

36 http://bmjopen.bmj.com/ 37 38 implemented in most of the primary hospitals, as they are limited by medical 39 40 condition, geographic location and techniques. Early thrombolysis and/or transfer PCI 41 42 43 strategy are the priority in these hospitals. Therefore, rapid identification of STEMI

44 on September 25, 2021 by guest. Protected copyright. 45 46 and referral to a hospital with PPCI ability are extremely important components in 47 48 establishing a regional STEMI care network in China. 49 50 51 Optimizing the in-hospital green channel can significantly shorten the 52 53 door-to-balloon (D2B) time and door-to-needle (D2N) time, while establishing a CPC 54 55 56 to integrate multiple resources is one of the most important methods [19 20]. 57 58 59 Traditional CPC focuses on the optimization and integration of the in-hospital sources 60 11

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4 aiming to shorten the time of the process. The medical system and patient factors BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 together determine the delay in STEMI emergency treatment [21]. The concept of a 8 9 modern CPC expands to establishing an effective regional network aiming to shorten 10 11 12 the total ischemia duration, thereby maximizing the advantage of reperfusion therapy. 13 14 The CPC independent accreditation in China was initiated in 2013 and 2 types 15 16 17 accreditation standards were developed according to PPCI ability [22 23]. 18 For peer review only 19 20 Procedures 21 22 The treatment process of patients suffered STEMI was based on the STEMI protocol 23 24 25 in the Announcement of Improving Medical Emergency Treatment Performance of 26 27 Acute Cardiovascular and Cerebrovascular Diseases issued by the National Health 28 29 30 Commission of China in 2015 [15]. Briefly, this flow chart included 1 center (EMS), 31 32 33 2 types of hospitals (PCI and non-PCI), 3 types of transfer methods (EMS transfer to 34 35 hospital, bypass emergency department (ED) and inter-hospital transfer), and 11

36 http://bmjopen.bmj.com/ 37 38 clinical pathways. Different clinical pathways were selected to execute the optimal 39 40 emergency treatment based on the approaching time, method and hospital ability 41 42 43 (Fig. 2). In addition, the procedures should be launched without results of myocardial

44 on September 25, 2021 by guest. Protected copyright. 45 46 biomarkers according to typical ischemic symptoms and electrocardiogram (ECG). 47 48 Data collection and management 49 50 51 Data of all treatment process were collected, including patient general information, 52 53 prehospital treatment, in-hospital management and follow-up management (Table 1). 54 55 56 Considering the real situation in ED, many time points could not be recorded 57 58 59 manually on time which might lead to missing and inaccurate data. Mobile device app 60 12

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4 can record these time variables through a simple click and complete the prehospital BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 ECG transmission. In addition, the technique of data auto-capture becomes 8 9 more and more popular at present and should resolve this issue. All of these methods 10 11 12 are considered gradually in this study. 13 14 Data were inputted into a self-built electronic database together with two existing 15 16 17 databases of both CPC accreditation and national PCI registry by trained clinical 18 For peer review only 19 20 research coordinators and clinicians in each hospital. The quality of the data was 21 22 monitored and suspicious contents with missing, outlier and logical errors were 23 24 25 mainly reviewed. When all problems are resolved, the database is then locked for 26 27 statistical analysis. 28 29 30 The describing method was used in CSCAP to mainly rank data quality and 31 32 33 medical quality. Continuous variables were described as mean (standard deviation) or 34 35 median (interquartile range), while categorical variables were described as a

36 http://bmjopen.bmj.com/ 37 38 percentage. Multivariate regression model was used to evaluate the factors related to 39 40 the assessment of medical quality. The Cox model was used to analyze the association 41 42 43 between exposures and medical outcomes. A P value < 0.05 was defined as a

44 on September 25, 2021 by guest. Protected copyright. 45 46 significant difference. All analyses were performed using R 47 48 (http://www.R-project.org). 49 50 51 Key performance index 52 53 The National Cardiovascular Data Registry (NCDR), established since 1997, has 54 55 56 become the basis for project implementation and quality evaluation as well as medical 57 58 59 quality improvement of research centers in the United States. It has a positive impact 60 13

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4 on clinical practice, medical payment, clinical research and government BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 decision-making [24 25]. The present study referred to the NCDR model to optimize 8 9 the STEMI quality of care and established an evaluation, feedback and improvement 10 11 12 system for primary key performance indexes (KPIs). For KPI selection, PPCI 13 14 hospitals focused on the improvement in the PPCI capacity and efficiency, non-PPCI 15 16 17 hospitals focused on the improvement in rapid diagnosis, thrombolysis and referral 18 For peer review only 19 20 capacity to PPCI hospitals, and EMS focused on the improvement in information 21 22 transmission to alert hospitals early for rapid and accurate transfer. 23 24 25 A total of 13 primary KPIs were selected for medical quality evaluation based on 26 27 different roles of EMS and hospitals in STEMI management (Table 2). However, 28 29 30 different treatment delay indexes were used in different phases according to the 31 32 33 progress of network construction. D2N and D2B time, defined as in-hospital FMC to 34 35 target vessel open, were used to evaluate in-hospital delay in CSCAP-1. First medical

36 http://bmjopen.bmj.com/ 37 38 contact-to-balloon (FMC2B) time and first medical contact-to-needle (FMC2N) time, 39 40 defined as FMC by emergency system or hospital to target vessel open, were used to 41 42 43 evaluate the whole medical system delay in CSCAP-2. Total ischemic time, defined

44 on September 25, 2021 by guest. Protected copyright. 45 46 as symptom onset to target vessel open, is used in CSCAP-3 to add the information of 47 48 patient delay. 49 50 51 The circular enrollment–evaluation–feedback-improvement method will be 52 53 implemented in both CSCAP-2 and CSCAP-3. The quality feedback report contains 54 55 56 each KPI of the affiliation and its ranking within its regional network and among all 57 58 59 affiliations. Comparisons of KPIs with itself and those of others are analyzed for 60 14

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4 tailed improvements. BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 8 Patient and public involvement 9 10 11 Public education of first aid and health care will be performed during the project 12 13 implementation. Patients were not offered the opportunity to participate in the study 14 15 16 design. They will obtain the information related to the study via public media as well 17 18 as academic publications.For peer review only 19 20 21 22 23 24 Ethics and dissemination 25 26 The study was conducted in accordance with Declaration of Helsinki. The study 27 28 29 protocol was approved by the Ethics Committee of Peking University First Hospital. 30 31 Ranking reports of quality of care will be made available to all participant affiliations. 32 33 34 Results will be disseminated at international conferences and published in 35

36 http://bmjopen.bmj.com/ 37 peer-reviewed scientific journals or public media. 38 39 40 41 Discussion 42 43 The integration and optimization of an integrated regional network with government

44 on September 25, 2021 by guest. Protected copyright. 45 46 support are urgent issues of STEMI care, especially in China. CSCAP is the first 47 48 prospective registry study focused on regional network construction and will help to 49 50 51 understand the current situations and the differences with other countries extensively, 52 53 which leading to optimized clinical practice and problem-guided improvement. It will 54 55 56 provide important information for the network construction shifting from the PPCI 57 58 59 hospital-centered regional network to the whole-city network step by step, so as to 60 15

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4 create an optimal integrate STEMI care system in China. BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 8 9 Contributions Yan Zhang coordinated the study, assisted with data collection, 10 11 12 performed data analysis, and drafted the manuscript. Bo Yu, Yaling Han, Jianan 13 14 Wang, Lixia Yang, Zheng Wan, Zheng Zhang, Yuguo Chen, Xianghua Fu, Chuanyu 15 16 17 Gao, Bao Li, Jiyan Chen, Ming Wu, Yitong Ma, Xingsheng Zhao, Yundai Chen, 18 For peer review only 19 20 Hongbing Yan, Dingcheng Xiang, Weiyi Fang, and Junbo Ge carried out the data 21 22 collection and helped draft the manuscript. Sameer Mehta and Christoph K Naber 23 24 25 participated in the design and helped draft the manuscript. Yong Huo, principal 26 27 investigator of the project, conceived and designed the project, helped collect data and 28 29 30 draft the manuscript. All authors reviewed the results and approved the final version 31 32 33 of the manuscript. 34 35

36 http://bmjopen.bmj.com/ 37 38 Acknowledgments 39 40 The authors thank the study team members and patient advisers of all 41 42 43 collaborative hospitals and emergency medical services. They are also grateful to the

44 on September 25, 2021 by guest. Protected copyright. 45 46 organizational coordination of Chinese Medical Doctor Association and China 47 48 Cardiovascular Association. They acknowledge the supports provided by the National 49 50 51 Health Commission and local governments in China. 52 53 54 55 56 Funding CSCAP was funded by Sanofi-Aventis, Abbott, and AstraZeneca. 57 58 59 Competing interests None declared. 60 16

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4 Patient consent for publication Not required. BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Ethics approval This study was reviewed and approved by the Ethics Committees 8 9 at Peking University First Hospital. 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

36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 17

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44 on September 25, 2021 by guest. Protected copyright. 45 46 (GWTG-CAD) registry. American heart journal 2011;162:988-95. e4. 47 48 49 50 51 52 53 54 55 56 57 58 59 60 21

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4 Table 1. CSCAP data elements BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Category Example elements 8 9 Patient baseline information Demographics (age, sex, ethnicity, region, occupation, 10 11 12 marriage status, and medical insurance type) 13 14 15 Risk factors (smoking status, BMI, hypertension, diabetes, 16 17 dyslipidemia, chronic kidney disease, peripheral artery 18 For peer review only 19 20 disease, MI history, stroke history, and prior 21 22 revascularization) 23 24 25 Clinical presentation (blood pressure, heart rate, and cardiac 26 27 28 function classification) 29 30 Prehospital information Patient (symptoms, symptom onset time, and hospital 31 32 33 approaching method) 34 35 EMS (response time, transfer process, first ECG time, ECG

36 http://bmjopen.bmj.com/ 37 38 transmission ratio, and bypass ED ratio) 39 40 41 Non-PCI hospital (hospital approaching method, first medical 42 43 contact time, admission time, first ECG time, diagnosis time,

44 on September 25, 2021 by guest. Protected copyright. 45 46 consent time, reperfusion and other treatment, DI-DO time, 47 48 and transfer process) 49 50 51 PCI hospital information Reperfusion (methods, indication and contraindication, and 52 53 54 nonreperfusion reasons) 55 56 Treatment delay (hospital approaching method, first medical 57 58 59 contact time, bypass ED ratio, admission time, first ECG time, 60 22

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4 catheter lab ready time, consent time, D2B, D2N, FMC2B, BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 FMC2N, total ischemic time, and reasons of delay) 8 9 PCI procedures (operative route, coronary angiography 10 11 12 results, aspiration, culprit vessels, stent, and elective PCI) 13 14 Thrombolytic procedures (thrombolytic agent, dose, and 15 16 17 outcome) 18 For peer review only 19 20 Medications (loading dose DAPT and statin, antiplatelets, 21 22 β-blockers, statin, ACEI/ARB, GP IIb/IIIa inhibitor, and 23 24 25 anticoagulant with dose and contraindication information) 26 27 Laboratory results (troponin, CK-MB, creatinine, HbA1c, 28 29 30 fasting glucose, BNP or NT-proBNP, lipid profiles, ECG, and 31 32 33 UCG) 34 35 Discharge (diagnosis, in-hospital duration, expense, and

36 http://bmjopen.bmj.com/ 37 38 medications) 39 40 Outcomes (death, non-fatal reinfarction, nonfatal stroke, 41 42 43 revascularization, mechanical complication, and bleeding)

44 on September 25, 2021 by guest. Protected copyright. 45 46 Follow-up and management Presentation status (symptom, cardiac function classification, 47 48 blood pressure, heart rate, and follow-up on-time ratio) 49 50 51 Laboratory results (lipid profiles, glucose traits, HbA1c, 52 53 creatinine, hemoglobin, BNP or NT-proBNP, ECG, and 54 55 56 UCG) 57 58 59 Medications (antiplatelets, β-blockers, statin, and ACEI/ARB) 60 23

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4 Risk factor control rate (Blood pressure, lipid, glucose, and BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 smoking cessation) 8 9 Outcomes (death, nonfatal reinfarction, stroke, 10 11 12 revascularization, rehospitalization due to unstable angina 13 14 pectoris, heart failure or other cardiovascular reasons, and 15 16 17 bleeding) 18 For peer review only 19 20 ACEI, Angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; 21 22 BMI, body mass index; BNP, brain natriuretic peptide; CK-MB, creatine kinase MB 23 24 25 isoenzyme; DAPT, dual antiplatelet therapy; D2B, door to balloon; D2N, door to 26 27 needle; DI–DO, door in–door out; ECG, electrocardiograph; ED, emergency 28 29 30 department; EMS, emergency medical service; FMC2B, first medical contact to 31 32 33 balloon; FMC2N, first medical contact to needle injection; GP IIb/IIIa, glycoprotein 34 35 IIb/IIIa; HbA1c, glycosylated hemoglobin A1c; MI, myocardial infarction;

36 http://bmjopen.bmj.com/ 37 38 NT-ProBNP, N-terminal pro–brain natriuretic peptide; PCI, percutaneous coronary 39 40 intervention; UCG, ultrasound cardiogram. 41 42 43

44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 24

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36 http://bmjopen.bmj.com/ 37 38 Discharge 39 40 41 Usage of both DAPT, statin, β blocker, and ACEI/ARB in patients without contraindication (%) 42 43 Outcomes

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36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 26

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4 Figure legends BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 5 6 7 Figure 1. CSCAP whole-city STEMI care network construction. 8 9 Figure 2. CSCAP STEMI emergency care flow chart. 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

36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

44 on September 25, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 27

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 29 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-026362 on 17 July 2019. Downloaded from 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 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

32 http://bmjopen.bmj.com/ 33 34 35 36 170x148mm (300 x 300 DPI) 37 38 39

40 on September 25, 2021 by guest. Protected copyright. 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