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Protocol for the Acute Myocardial Infarction Study in Northeastern China (AMINoC): a real-world prospective cohort study ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2020-042936

Article Type: Protocol

Date Submitted by the 20-Jul-2020 Author:

Complete List of Authors: Li, Tianyi; Jilin University Second Hospital, cardiology Wu, Junduo; Jilin University Second Hospital, cardiology Liu, Jia; Jilin University Second Hospital, Cardiology Sun, Wei; the Second Hospital of Jilin University, cardiology Qi, Chao; Jilin University Second Hospital, Cardiology Liu, Bin; Jilin University Second Hospital, Department of Cardiology Wells, George ; University of Ottawa, School of Epidemiology and Public Health; University of Ottawa Heart Institute, Cardiovascular Research Methods Centre Wang, Junnan; Jilin University Second Hospital, Cardiology

Myocardial infarction < CARDIOLOGY, EPIDEMIOLOGY, Protocols & Keywords:

guidelines < HEALTH SERVICES ADMINISTRATION & MANAGEMENT http://bmjopen.bmj.com/

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1 2 3 4 Protocol for the Acute Myocardial Infarction Study in Northeastern China 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 7 (AMINoC): a real-world prospective cohort study 8 9 Tianyi Li1, Junduo Wu1, Jia Liu1, Wei Sun1, Chao Qi1, Bin Liu1, George Wells2, 10 11 Junnan Wang*, on behalf of Acute Myocardial Infarction Study in Northeastern 12 13 China (AMINoC) 14 15 16 17 1 Department of Cardiology, The Second Hospital of Jilin University, Changchun, 18 For peer review only 19 Jilin, China 20 21 2 Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, 22 23 Ottawa, Canada 24 25 26 27 28 *Corresponding author 29 30 Email adress: [email protected] 31 32 33 34 Word count (excluding title page, abstract, references, figures and tables): 2942 35 36

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1 2 3 4 Abstract 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 Introduction: Acute myocardial infarction (AMI) has become one of the major 7 8 causes of mortality and morbidity in China. However, little is known about the 9 10 characteristics, medical care, and outcomes of AMI patients in northeastern China. 11 The Acute Myocardial Infarction Study in Northeastern China (AMINoC) is aimed at 12 13 obtaining timely real-world knowledge in terms of characteristics, clinical care, and 14 15 outcomes of AMI patients and at providing care-quality improvement efforts in 16 17 northeastern China. 18 For peer review only 19 Methods and analysis: The AMINoC is a real-world, prospective, multicenter cohort 20 21 study. The study selected 20 hospitals using stratified cluster sampling from different 22 23 levels of hospitals among nine districts throughout Jilin Province. Hospitalized 24 25 patients with a primary diagnosis of AMI in each site are consecutively enrolled for 1 26 27 year. Demographic characteristics, clinical data, treatments, outcomes, and cost are 28 29 collected by local investigators. Patient follow-up after discharge is planned for up to 30 31 2 years. 32 33 Ethics and dissemination: The protocol has been approved by the ethics committee 34 35 at the Second Hospital of Jilin University. The findings of this study will be published 36

37 in peer-reviewed journals and medical conferences. http://bmjopen.bmj.com/ 38 39 Registration: The study is registered at Clinical Trials (NCT 04451967). 40 41 Keywords: acute myocardial infarction, prospective, observational, protocol, 42 43 44

45 Strengths and limitations of this study on October 1, 2021 by guest. Protected copyright. 46 47  This is a real-world, multicenter, prospective study of hospitalized AMI patients 48 49 throughout northeastern China. 50  A comprehensive understanding of the epidemiology, real-world clinical practice, 51 52 outcomes, and medical cost of hospitalized AMI patients in northeastern China 53 54 will be obtained from this study. 55 56  Possible heterogeneity of patients and practices may influence some aspects of 57 58 the data collection. 59 60

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1 2 3 4 INTRODUCTION 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 Acute myocardial infarction (AMI) is among the leading causes of morbidity and 7 8 mortality worldwide, with more than 7 million cases annually,[1] thus causing a great 9 10 economic burden. Although AMI mortality has been reduced in western countries 11 during the past decades due to evidence-based therapies,[1-3] the incidence of AMI is 12 13 increasing sharply in China.[4] Several factors are responsible for this increase: first, 14 15 improving medical care decreased the mortality of infectious diseases, leading to a 16 17 shift of the main disease burden in China from infectious diseases to non-infectious 18 For peer review only 19 diseases, including AMI;[5] second, with the increase in lifespan and economic 20 21 development, the prevalence of non-infectious diseases such as hypertension, 22 23 diabetes, and hyperlipidemia, many of which are risk factors of AMI, steadily 24 25 increased during the past decades;[6] lastly, as the increasing urbanization and 26 27 lifestyle of Chinese residents tend to have less physical activity and more cigarette 28 29 and alcohol consumption,[7, 8] all of which are risk factors for cardiovascular disease. 30 31 Despite the increasing incidence of AMI in China, medical care has not improved 32 33 accordingly. Moreover, as economic development differs in urban and rural areas, 34 35 hospital levels vary, and the medical care received by AMI patients may also 36

37 differ.[9] Hospitals in China are classified as primary (community hospitals with only http://bmjopen.bmj.com/ 38 39 the most basic facilities and with very limited inpatient capacity), secondary (hospitals 40 41 with at least 100 inpatient beds providing acute medical care and preventative care 42 43 services to populations of at least 100,000), or tertiary (major tertiary referral centers 44

45 in provincial capitals and major cities) according to the Chinese National Health on October 1, 2021 by guest. Protected copyright. 46 47 Commission.[10] Urban areas have tertiary hospitals where AMI patients can directly 48 49 undergo primary percutaneous coronary intervention (PCI) treatment after 50 hospitalization, whereas in rural areas with a less developed economy, secondary 51 52 hospitals are the largest available hospitals, some of which are not capable of 53 54 performing primary PCI. Under this circumstance, AMI patients have to be 55 56 transferred to a tertiary hospital to obtain PCI treatment. Moreover, some patients may 57 58 be misdiagnosed or appropriate treatments in clinical practice may be delayed.[11, 12] 59 60 The increasing prevalence of AMI and inappropriate medical care indicate a severe

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1 2 3 4 AMI situation in China. 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 The government has been increasingly focusing on the AMI situation in China. 7 8 During the past several years, some large-scale epidemiology studies, for example, 9 10 CHINA PEACE[13] and CAMI,[14] have been conducted to better understand the 11 AMI situation in China. However, as the economic and geographic situations vary 12 13 largely across the country, a deep understanding of different regional AMI situations 14 15 is urgently needed in order to develop targeted policies. Jilin Province is located at the 16 17 center of northeastern China, with unique features in comparison with the rest of 18 For peer review only 19 China. Like other provinces of northeastern China, Jilin Province has a relatively cold 20 21 climate, less developed economy, and greatly unbalanced economic development 22 23 between urban and rural areas. The residents tend to have a higher in-salt diet and less 24 25 physical activities than those in southern parts of China. These facts indicate that AMI 26 27 is a growing problem in northeastern China. However, to the best of our knowledge, 28 29 provincial AMI epidemiologic data are lacking. Therefore, we designed the Acute 30 31 Myocardial Infarction Study in Northeastern China (AMINoC), a real-world 32 33 prospective cohort study, as an integrated research in order to address the current 34 35 knowledge gap of AMI situations in northeastern China, and generate knowledge 36

37 about the characteristics, clinical care, and outcomes of hospitalized AMI patients and http://bmjopen.bmj.com/ 38 39 provide a deep understanding of education, prevention, and treatment of the AMI 40 41 patinets in the province of Jilin. We herein present the protocol for the AMINoC 42 43 study. 44

45 on October 1, 2021 by guest. Protected copyright. 46 47 METHODS AND ANALYSIS 48 49 Objectives of the AMINoC study 50 The specific aims of our study are to describe the characteristics of hospitalized 51 52 AMI patients in Jilin Province, including their demographic and clinical attributes; 53 54 characterize patterns of in-hospital treatment; describe in-hospital mortality and 55 56 morbidity rates (i.e., outcomes); determine trends in patient characteristics, clinical 57 58 care, and outcomes over time; develop and test prognostic models for risk 59 60 stratification; compare treatment across districts in Jilin Province and determine

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1 2 3 4 whether different therapy patterns by setting may be associated with different 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 outcomes; compare diagnostic testing done to the testing guidelines and compare 7 8 treatments prescribed to the treatment guidelines; describe and compare 9 10 characteristics, treatment, and outcomes of AMI patients between different sexes; 11 describe and compare characteristics, treatments and outcomes of AMI patients 12 13 between urban and rural areas; compare characteristics, treatments, and outcomes of 14 15 AMI patients following different hospital transfer methods to a tertiary hospital such 16 17 as direct transfer to a tertiary hospital versus transfer after thrombolysis or 18 For peer review only 19 anti-platelet therapy and transfer to a tertiary hospital after thrombolysis versus 20 21 transfer after anti-platelet therapy. 22 23 24 25 Design overview 26 27 This real-world prospective cohort study is both descriptive and inferential and 28 29 includes information on hospitalizations with AMI diagnosis, including ST-segment– 30 31 elevation myocardial infarction (STEMI) and non-ST-segment–elevation myocardial 32 33 infarction (NSTEMI). We did not include hospitalizations with a principal discharge 34 35 diagnosis of unstable angina. 36

37 The ethics committee at the Second Hospital of Jilin University approved the http://bmjopen.bmj.com/ 38 39 AMINoC. 40 41 42 43 Sampling design 44

45 We intended to include study hospitals that reflect both urban and rural sites of on October 1, 2021 by guest. Protected copyright. 46 47 care in Jilin Province. As hospital volumes and clinical capacities differ between 48 49 urban and rural areas, we separately identified hospitals in those areas. An urban area 50 was defined as downtown or suburban area within a directly controlled autonomous 51 52 prefecture (Yanbian Korean Autonomous Prefecture). A rural area was defined as the 53 54 surrounding county-level regions, including counties and county-level cities. Under 55 56 this framework, Jilin Province is composed of nine districts, and each district 57 58 comprises an urban area and a few rural areas. 59 60 We identified patients for study inclusion using a stratified cluster sampling

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1 2 3 4 design. With nine districts, which each district has an urban stratum and rural strata, 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 we yielded 18 strata. We identified hospitals within each stratum as follows. In the 7 8 rural area within a district, we used a random number table to order the legible central 9 10 secondary hospitals to determine the order in which the hospitals would be 11 approached for enrollment in the study; once a hospital agreed, the remaining 12 13 hospitals would not be approached. In an urban area within a district, we enrolled the 14 15 largest tertiary hospital as defined by the number of cardiovascular beds. If there were 16 17 two hospitals of the same bed size, we ordered the hospitals using a random number 18 For peer review only 19 table and they would be approached for enrollment in the study following this order, 20 21 with the first hospital to agree being enrolled in the study. Considering that the 22 23 population in Changchun City and Jilin City, both of which are urban areas within 24 25 two different districts, is much larger than that of other urban areas, two tertiary 26 27 hospitals from each area were randomly selected. Prison hospitals, traditional Chinese 28 29 medicine hospitals, specialized hospitals without a cardiovascular disease division, 30 31 and military hospitals were excluded. 32 33 34 35 Patient population and inclusion criteria 36

37 All eligible and consenting AMI patients admitted to each of the selected http://bmjopen.bmj.com/ 38 39 hospitals will be enrolled in a consecutive fashion for 1 year. The sample size of each 40 41 hospital was determined based on the experience of the Second Hospital of Jilin 42 43 University (78% of beds for AMI patients in a month) and the number cardiovascular 44

45 inpatient beds. The estimated sample size was 3336 patients, with 2124 from territory on October 1, 2021 by guest. Protected copyright. 46 47 hospitals in urban areas and 1212 from secondary hospitals in rural areas (Table 1). 48 49 50 Table 1 Estimated sample size of each site 51 52 Estimated sample Estimated sample Site 53 amount (patients/month) amount (patients/year) 54 55 Yanbian University Hospital 15 180 56 Dunhua City Hospital in Jilin Province 11 132 57 58 Liaoyuan City Central Hospital 11 132 59 60 Dongliao People’s Hospital 7 84

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1 2 3 Songyuan Central Hospital 14 168 4 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 5 Changling People’s Hospital 8 96 6 7 Siping Central Hospital 16 192 8 The First People’s Hospital of Manchu 9 8 96 10 Autonomous County 11 The Second Hospital of Jilin 12 34 408 University 13 14 Changchun Center Hospital 12 144 15 16 Nongan People’s Hospital 16 192 17 Affiliated Hospital of Beihua 18 29 348 University For peer review only 19 Jilin Hospital of Integrated Traditional 20 10 120 21 Chinese and Western Medicine 22 23 Panshi City Hospital 22 264 24 Tonghua Central Hospital 15 180 25 26 Baishan Central Hospital 9 108 27 28 Jingyu People’s Hospital 8 96 29 30 Meihekou Central Hospital 8 96 31 Baicheng Central Hospital 12 144 32 33 Tongyu First Hospital 13 156 34 35 Total 278 3336 36

37 http://bmjopen.bmj.com/ 38 39 Eligible patients must be admitted within 7 days of acute myocardial ischemic 40 41 symptoms with a primary clinical diagnosis of AMI, including STEMI or NSTEMI. 42 43 The final inclusion criterion is the Fourth Universal Definition for Myocardial 44 Infarction (2018).[15] Types 1, 2, 3, and types 4b and 4c are included in the present 45 on October 1, 2021 by guest. Protected copyright. 46 study according to the classification of myocardial infarction. Types 4a and type 5 are 47 48 not eligible for the AMINoC study. 49 50 51 52 Data collection 53 54 The input feasibility and data collection burden were discussed among the 55 56 principal investigators, statisticians, data managers, clinical and research experts of 57 58 the Scientific Committee and Executive and Steering Committee, and AMINoC Study 59 60 investigators to develop and determine the data elements collected in the study.

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1 2 3 4 Standardized data collected encompassed demographic characteristics, medical 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 history, clinical presentation, risk factors, physical examination, laboratory values, 7 8 imaging results, reperfusion strategies, medications, transfer strategies, clinical 9 10 events, and cost (Table 2). 11 12 13 Table 2 Examples of data elements 14 15 16 Category Contents/example elements 17 Age, sex, social ID, race, occupation, education, marriage, 18 Patient demographicsFor peer review only 19 insurance 20 Clinical presentation Symptoms, time of presentation, triggering factors 21 22 Initial medical contact First medical contact, transfer information, cardiac status 23 Hypertension, diabetes, prior cardiovascular disease, prior 24 Medical history and 25 revascularization, chronic kidney disease, lung disease, smoking, risk factors 26 alcohol 27 Reperfusion strategy Thrombolysis, primary and rescue PCI, selected PCI, 28 29 for STEMI complications, CABG 30 Revascularization for PCI, risk stratification, complications 31 NSTEMI 32 33 Antiplatelet, heparin, statin, β -blocker, CCB, ACEI/ARB, 34 Medications 35 anticoagulant, platelet GP IIb/IIIa receptor inhibitor 36 Mechanical 37 IABP, ECMO, LVAD http://bmjopen.bmj.com/ 38 circulatory support 39 Lab results Cardiac biomarkers, NT-proBNP, BNP, Creatinine, LVEF 40 41 Death, heart failure, re-infarction, cardiac shock, atrial fibrillation, In-hospital outcomes 42 malignant arrhythmia, cardiac arrest, stroke, major bleeding events 43 44 Discharge Discharge status, cost, medications

45 Vital status, medications, clinical events including death, MI, heart on October 1, 2021 by guest. Protected copyright. 46 Follow-up failure, arrhythmia, revascularization 47 48 PCI, Percutaneous Coronary Intervention; CABG, coronary artery bypass graft; CCB, calcium 49 channel blocker; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor 50 blocker; GP, glycoprotein; IABP, Intra-Aortic Balloon Pump; ECMO, extracorporeal membrane 51 52 oxygenation; LVAD, Left Ventricular Assist Device; NT-proBNP, N-terminal pro-brain 53 natriuretic peptide; BNP, brain natriuretic peptide; LVEF, left ventricular ejection fraction 54 55 56 57 Data are collected, validated, and submitted by trained staff from each site using a 58 59 secure, password-protected, web-based electronic data capture (EDC) system. For 60

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1 2 3 4 each patient meeting the inclusion criteria, the demographic characteristics must be 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 filled in using an electronic case report form (eCRF) and submitted online within 24 h 7 8 from admission. A unique ID will be assigned to each patient through the patient’s 9 10 social ID number to avoid duplication. Site investigators are required to collect all the 11 data during the hospitalization and complete and submit the eCRF within 24 h after 12 13 the patient’s discharge or death. Data input tracking, regular alerts, rigorous data 14 15 monitoring, and queries are used to support timely and accurate completion of the 16 17 eCRF. 18 For peer review only 19 20 21 Patient follow-up 22 23 When a patient is discharged, he or she receives specific guidance on healthy 24 25 lifestyle and medication. Follow-up visits are planned at 30 days and at 3, 6, 12, 18, 26 27 and 24 months via either clinic visit or telephone call. The symptoms, medication, 28 29 reasons for medication discontinuation and clinical events (including cardiovascular 30 31 events, death, bleeding events, and so on), will be reviewed and collected. For clinical 32 33 events, source documents are required for validation. 34 35 36

37 http://bmjopen.bmj.com/ 38 39 Data management 40 41 The whole eCRF must be filled out for each eligible/included patient by 42 43 investigators at the corresponding site. Web-based data entry access is 44

45 password-restricted to trained personnel at each site. Data are continuously cleaned on October 1, 2021 by guest. Protected copyright. 46 47 systematically. To control the data quality continuously, real-time automated range 48 49 and logic check at the data entry for the validity and completeness are integrated in 50 the EDC system. For any queries about the data validity or logic, data managers can 51 52 query and validate according to the answers provided by corresponding investigator 53 54 via the EDC system. Queries can be reissued if necessary. 55 56 57 58 Progress to date 59 60 The AMINoC was launched on 9 September 2019 among a total of 20 hospitals

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1 2 3 4 in Jilin Province, including 11 in urban areas and 9 in rural areas (Fig. 1). 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 As of 9 June 2020, 1,485 patients have been enrolled in the AMINoC study. 7 8 9 10 Statistical analysis 11 We will report the summary statistics for patient characteristics, use of diagnostic 12 13 tests, treatments received, and in- and out-hospital outcomes including complications 14 15 of care across study sites. All data will be weighted to be representative of Jilin 16 17 Province. 18 For peer review only 19 For observational data, standard parametric and nonparametric techniques, 20 21 including student t tests, χ2 tests, generalized linear models, and Wilcoxon rank-sum 22 23 tests, will be used for each aim. Considering the correlation of patient characteristics, 24 25 clinical care, and outcomes within study sites, the effect of clustering will be 26 27 accounted for in the analyses. To examine and adjust for differences between the 28 29 comparison groups, linear, logistic, Cox proportional hazard, and Poisson models with 30 31 a generalized estimating equation approach and hierarchical models, will be used 32 33 where appropriate. Models will be developed to stratify the risk of adverse outcomes 34 35 of AMI patients. To assess the relationship between candidate variables and clinical 36

37 outcomes, appropriate statistical techniques will be performed for the dependent http://bmjopen.bmj.com/ 38 39 variable. The list of candidate variables will be furthered refined according to their 40 41 clinical relevance. 42 43 44

45 Patient and public involvement on October 1, 2021 by guest. Protected copyright. 46 47 The patients and public were not involved in the design, recruitment, and 48 49 conduction of the study. 50 51 52 ETHICS AND DISSEMINATION 53 54 The AMINoC Study is approved by the ethics committee of the Second Hospital 55 56 of Jilin University. Any amendments to the research protocol will be submitted for 57 58 ethical approval. There are no safety concerns for enrolled patients. There is a waiver 59 60 of informed consent for this observational, non-interventional study in all centers

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1 2 3 4 The findings of this study will be published in peer-reviewed journals and 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 medical conferences. 7 8 9 10 Discussion 11 The AMINoC study is a large-scale, comprehensive, multicenter, real-world 12 13 study on AMI epidemiology in northeastern China that will provide a platform for 14 15 understanding and assessing AMI medical practice, medical care improvement, 16 17 translational medicine, and prevention. 18 For peer review only 19 Through the AMINoC study, it will be possible to obtain a comprehensive and 20 21 continuous understanding of epidemiology, real-world clinical treatment, outcomes, 22 23 and cost of hospitalized AMI patients in northeastern China in real time, and compare 24 25 those with other parts of China and other countries. We will obtain demographic 26 27 characteristics, medical histories, lifestyle characteristics, and clinical presentations. 28 29 All these information will help in understanding the distributions and features of 30 31 hospitalized AMI patients. 32 33 The AMINoC provides a platform to evaluate the clinical therapy of AMI 34 35 patients at different hospital levels. Clinicians might make different diagnosis and 36

37 treatment decisions in clinical practice;[16] some may even misdiagnose or administer http://bmjopen.bmj.com/ 38 39 inappropriate treatment. This study will collect and evaluate data on all the clinical 40 41 testing, diagnosis, and treatment decisions made by clinicians in different levels of 42 43 hospitals and compare the clinical practice to prescribed AMI guidelines. This will 44

45 provide a better understanding of the current clinical practice in different level on October 1, 2021 by guest. Protected copyright. 46 47 hospitals and districts. 48 49 This study is also an inferential study on the outcomes of different therapeutic 50 strategies and transfer strategies. We will obtain short- and long-term outcomes of 51 52 AMI patients undergoing different therapeutic strategies, including primary PCI, 53 54 delayed PCI, thrombolysis, non-reperfusion therapy, and so on. Analysis of these data 55 56 will help to assess different therapeutic strategies for different AMI patients 57 58 subgroups. We will also determine the short- and long-term outcomes of AMI patients 59 60 undergoing different transfer strategies from a secondary hospital to a territory

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1 2 3 4 hospital. These data will help provide advice for optimum safety and more effective 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 transfer strategies in clinical practice. This comprehensive analysis will help in 7 8 constructing a regional collaborative rapid-treatment system among different levels of 9 10 hospitals in different districts in Jilin Province, thus promoting medical care and 11 improving the outcomes of AMI patients. 12 13 The AMINoC also provides data to help promote the understanding of AMI 14 15 patient management among administrative personnel. Chest pain center is considered 16 17 to be an effective mode for early diagnosis and treatment of AMI.[17, 18] The 18 For peer review only 19 Chinese Society of Cardiology has been processing and constructing chest pain 20 21 centers throughout country during the past few years.[19, 20] However, the effects 22 23 and benefits of chest pain centers in China are not clear. Among the 20 hospitals 24 25 enrolled in the study, some are chest pain centers, whereas others are not. This study 26 27 will provide data to compare the real-world clinical practice between chest pain 28 29 centers and non-chest pain centers. These results will help in evaluating the effect of 30 31 chest pain center in the real world and in understanding the factors associated with 32 33 delay in AMI management. This will promote management of AMI patients at the 34 35 hospital level. 36

37 The AMINoC also helps in making specific guidance to educate patients and http://bmjopen.bmj.com/ 38 39 clinicians. Through this study, we will acquire data about the public understanding of 40 41 AMI and response to AMI and the medical adherence of AMI patients. We hope to 42 43 establish a platform to help make specific guidance to educate the public about AMI 44

45 knowledge, promote prevention and early recognition of AMI, and increase the on October 1, 2021 by guest. Protected copyright. 46 47 adherence of AMI patients. Meanwhile, this study will acquire data about the clinical 48 49 practice of AMI in different levels of hospitals, which will provide quality feedback 50 and scientific support to educate clinicians, including cardiologists and emergency 51 52 departments, to reduce misdiagnosis and delayed diagnosis, and to promote standard 53 54 AMI management. 55 56 The AMINoC study has some potential limitations. Heterogeneity of patients and 57 58 practices among the 20 sites is expected. This was minimized by standardized tools 59 60 and training for research staff and data collection. Furthermore, although prospective

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1 2 3 4 cohort studies allow for identification of risk factors, there is the potential to identify 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 spurious associations. 7 8 9 10 Collaborators 11 Cui Lan and Li Yuzi, Department of Cardiology, Yanbian University Hospital, 12 13 Yanbian, China; Meng Fanju, Department of Cardiology, Dunhua City Hospital in 14 15 Jilin Province, Dunhua, China; Guo Chaoyang, Department of Cardiology, Liaoyuan 16 17 City Central Hospital, Liaoyuan, China; Shi Li, Department of Cardiology, Dongliao 18 For peer review only 19 People’s Hospital, Liaoyuan, China; Yuan Limei, Zhen Yi, and Yuan Lijuan, 20 21 Department of Cardiology, Songyuan Central Hospital, Songyuan, China; Li Shiying, 22 23 Department of Cardiology, Changling People’s Hospital, Songyuan, China; Li 24 25 Mingzhe and Fang Zhihua, Department of Cardiology, Siping Central Hospital, 26 27 Siping China; Sui Yanlong, Department of Cardiology, The First People’s Hospital of 28 29 Manchu Autonomous County, Siping, China; Gong Junli and Hou Fengxia, 30 31 Department of Cardiology, Changchun Center Hospital, Changchun, China; Zhang 32 33 Limei and Zhu dayong, Department of Cardiology, Nongan People’s Hospital, 34 35 Changchun, China; Xu Lihua, Sun Feng, Ding Fuxiang, Gu Ming, and Liao Xudong, 36

37 Department of Cardiology, Affiliated Hospital of Beihua University, Jilin, China; Jin http://bmjopen.bmj.com/ 38 39 Guangfen, Department of Cardiology, Panshi City Hospital, Jilin, China; Shi Liping, 40 41 Department of Cardiology, Jilin Hospital of Integrated Traditional Chinese and 42 43 Western Medicine, Jilin, China; Zhang Xuxia, Department of Cardiology, Tonghua 44

45 Central Hospital, Tonghua, China; Zhuang Maojun, Baishan Central Hospital, on October 1, 2021 by guest. Protected copyright. 46 47 Baishan, China; Lin Yuhui, Jingyu People’s Hospital, Baishan, China; Zhang 48 49 Jinliang, Department of Cardiology, Meihekou Central Hospital, Meihekou, China; 50 Wang Qi, Department of Cardiology, Baicheng Central Hospital, Baicheng, China; Qi 51 52 Dejie, Department of Cardiology, Tongyu First Hospital, Baicheng, China. 53 54 55 56 Competing interests: 57 58 None declared. 59 60

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1 2 3 4 Funding: 5 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 This work was supported by Jilin Provincial Science and Technology Department 7 8 (NO. 20190905002SF, NO. 20170204032YY) and the National Clinical Key 9 10 Specialty Project 11 12 13 Authors’ contributions: 14 15 Conception and design: BL, JNW, TYL, and JDW. Acquisition, analysis and 16 17 interpretation of the data: TYL, JL, WS, and QC. Analysis of the data: TYL, GW. 18 For peer review only 19 Drafting the manuscript: TYL. Critiquing the manuscript: TYL, JNW, and JDW. All 20 21 authors provided fnal approval of the manuscript. 22 23 24 25 Data availability statement 26 27 Data are available on reasonable request. All data generated analysed during the 28 29 current study are avilable from the corresponding author on reasonable request. 30 31 32 33 34 35 36

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

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1 2 3 4 References BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 5 1. Reed GW, Rossi JE, Cannon CP. Acute myocardial infarction. The Lancet. 2017; 389 6 7 (10065):197-210. 8 2. Rogers WJ, Frederick PD, Stoehr E, Canto JG, Ornato JP, Gibson CM, et al. Trends in presenting 9 characteristics and hospital mortality among patients with ST elevation and non-ST elevation 10 myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart 11 12 J. 2008; 156 (6):1026-34. 13 3. Laribi S, Aouba A, Resche-Rigon M, Johansen H, Eb M, Peacock F, et al. Trends in death 14 attributed to myocardial infarction, heart failure and pulmonary embolism in Europe and Canada over 15 16 the last decade. QJM: An International Journal of Medicine. 2014; 107 (10):813-20. 17 4. Li J, Li X, Wang Q, Hu S, Wang Y, Masoudi FA, et al. ST-segment elevation myocardial 18 infarction in ChinaFor from 2001 peer to 2011 (the reviewChina PEACE-Retrospective only Acute Myocardial Infarction 19 20 Study): a retrospective analysis of hospital data. The Lancet. 2015; 385 (9966):441-51. 21 5. Yang G, Wang Y, Zeng Y, Gao GF, Liang X, Zhou M, et al. Rapid health transition in China, 22 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet. 2013; 381 23 (9882):1987-2015. 24 25 6. Yang G, Kong L, Zhao W, Wan X, Zhai Y, Chen LC, et al. Emergence of chronic 26 non-communicable diseases in China. Lancet. 2008; 372 (9650):1697-705. 27 7. Sheng Shou HU, Kong LZ, Gao RL, Zhu ML, Wang W, Wang YJ, et al. Outline of the Report on 28 29 Cardiovascular Disease in China, 2010. Biomedical & Environmental Sciences. 2012; 25 (3):251-6. 30 8. Cheng-Fu C, Jing-Yi R, Xiang-Hai Z, Su-Fang L, Hong C. Twenty-year trends in major 31 cardiovascular risk factors in hospitalized patients with acute myocardial infarction in Beijing. Chinese 32 33 medical journal. 2013; 126 (22):4210-5. 34 9. C-Y L, Y-N L, C-L L, Y-J C, Y-H H, W-C T, et al. Cardiologist service volume, percutaneous 35 coronary intervention and hospital level in relation to medical costs and mortality in patients with acute 36 myocardial infarction: a nationwide study. QJM. 2014; 107 (7):557-64. 37 http://bmjopen.bmj.com/ 38 10. China UNHPGi. A Health Situation Assessment of the People’s Republic of China. UNHPG 39 Beijing; 2005. 40 11. Gao R, ., Patel A, ., Gao W, ., Hu D, ., Huang D, ., Kong L, ., et al. Prospective observational 41 42 study of acute coronary syndromes in China: practice patterns and outcomes. Heart. 2008; 94 43 (5):554-60. 44 12. Ranasinghe I, Rong Y, Du X, Wang Y, Gao R, Patel A, et al. System Barriers to the

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1 2 3 patients with acute coronary syndromes at the time of hospital discharge and 1 year after 4 5 hospitalization: results from the Clinical Pathways for Acute Coronary Syndromes in China (CPACS) BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 6 study. American heart journal. 2009; 157 (3):509-16. e1. 7 17. Keller T, Post F, Tzikas S, Schneider A, Arnolds S, Scheiba O, et al. Improved outcome in acute 8 coronary syndrome by establishing a chest pain unit. Clinical research in cardiology. 2010; 99 9 10 (3):149-55. 11 18. Steurer J, Held U, Schmid D, Ruckstuhl J, Bachmann LM. Clinical value of diagnostic 12 instruments for ruling out acute coronary syndrome in patients with chest pain: a systematic review. 13 14 Emergency Medicine Journal. 2010; 27 (12):896-902. 15 19. Dingcheng X, Shaodong Y. Chest pain centers in China: Current status and prospects. Cardiology 16 Plus. 2017; 2 (2):18. 17 18 20. Fan F, Li Y, ForZhang Y, Lipeer J, Liu J, Hao review Y, et al. Chest Pain only Center Accreditation Is Associated 19 With Improved In‐Hospital Outcomes of Acute Myocardial Infarction Patients in China: Findings 20 From the CCC‐ACS Project. Journal of the American Heart Association. 2019; 8 (21):e013384. 21 22 23 24 25 26 Figure legends 27 28 Figure 1 Geographic distribution of hospitals throughout the Jilin Province 29 30 31 32 33 34 35 36

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1 BMJ Open: first published as 10.1136/bmjopen-2020-042936 on 25 May 2021. Downloaded from 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 Geographic distribution of hospitals throughout the Jilin Province 31 32

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