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Use of Intravenous Magnesium Sulfate among Patients with Acute Myocardial Infarction in China from 2001 to 2015: China PEACE-Retrospective AMI Study ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-033269

Article Type: Original research

Date Submitted by the 29-Jul-2019 Author:

Complete List of Authors: Wang, Xianqiang; National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China Du, Xue; National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China Yang, Hao; National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical http://bmjopen.bmj.com/ Sciences and Peking Union Medical College, Beijing, People's Republic of China Bucholz, Emily ; Center for Outcomes Research and Evaluation, Yale- New Haven Hospital Downing, Nicholas ; Center for Outcomes Research and Evaluation, Yale- New Haven Hospital Spertus, John; St. Luke's Mid America Heart Institute, Cardiovascular Outcomes Research

Masoudi, Fredrick; University of Colorado Anschutz Medical Campus, on September 25, 2021 by guest. Protected copyright. Medicine Li, Jing; National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China Guan, Wenchi; National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China Gao, Yan; National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China Hu, Shuang; National Clinical Research Center of Cardiovascular

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1 2 3 Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai 4 Hospital, National Center for Cardiovascular Diseases, Chinese Academy 5 of Medical Sciences and Peking Union Medical College, Beijing, People's 6 Republic of China 7 Bai, Xueke; National Clinical Research Center of Cardiovascular Diseases, 8 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National 9 Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of 10 China 11 Krumholz, Harlan; Yale-New Haven Hospital Center for Outcomes 12 Research and Evaluation, 13 Li, Xi; National Clinical Research Center of Cardiovascular Diseases, 14 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National 15 Center for Cardiovascular Diseases, Chinese Academy of Medical 16 Sciences and Peking Union Medical College, Beijing, People's Republic of For peerChina review only 17 18 Keywords: acute myocardial infarction, Magnesium Sulfate, quality of health care 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 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 75

1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 Use of Intravenous Magnesium Sulfate among Patients with Acute Myocardial

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 Infarction in China from 2001 to 2015: China PEACE-Retrospective AMI Study 6 7 3 8 9 10 4 Running head: Magnesium Sulfate for AMI in China 11 12 5 13 14 6 Xianqiang Wang*, MD; Xue Du*, MD; Hao Yang; Emily Bucholz, MD PhD; Nicholas 15 16 7 Downing, MD; John A. Spertus, MD, MPH; Frederick A Masoudi, MD, MSPH; Jing Li, 17 18 8 MD, PhD; WenchiFor Guan, peer MD; Yan Gao; review Shuang Hu, PhD;only Xueke Bai, MS; Harlan M. 19 20 9 Krumholz#, MD SM; Xi Li#, PhD; for the China PEACE Collaborative Group (see 21 22 10 Appendix A) 23 24 11 25 26 12 * Contribute equally 27 28 # Co-senior authors 29 13 30 31 14 32 33 15 National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory 34 35 16 of Cardiovascular Disease (XW, XD, HY, JL, WG, YG, SH, XB, XL), Fuwai Hospital, 36 37 17 National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences http://bmjopen.bmj.com/ 38 39 18 and Peking Union Medical College, Beijing, People's Republic of China; 40 41 19 Saint Luke’s Mid America Heart Institute and the University of Missouri-Kansas City 42 43 20 (JAS), Kansas City, Missouri, United States; 44 on September 25, 2021 by guest. Protected copyright. 45 21 Division of Cardiology (FAM), University of Colorado Anschutz Medical Campus, 46 47 22 Aurora, Colorado, United States; 48 49 50 23 Center for Outcomes Research and Evaluation (HMK, EB, ND), Yale-New Haven 51 52 24 Hospital, New Haven, Connecticut, United States; Section of Cardiovascular 53 54 25 Medicine (HMK), Robert Wood Johnson Clinical Scholars Program (HMK), 55 56 26 Department of Internal Medicine, Yale University School of Medicine, New Haven, 57 58 27 Connecticut, United States; Department of Health Policy and Management (HMK), 59 60 28 Yale School of Public Health, New Haven, Connecticut, United States.

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1 2 3 Correspondence: Dr Xi Li, National Clinical Research Center of Cardiovascular

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 Diseases, Fuwai Hospital, 167 Beilishi Road, Beijing 100037, People’s Republic of 6 7 3 China; Tel: +86 10 8839 6203; Fax: +86 10 8836 5201; 8 9 10 4 Email: [email protected] 11 12 5 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 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 ABSTRACT

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 Objective 6 7 3 To assess the trends and variation in use of IV magnesium sulfate among patient 8 9 10 4 with acute myocardial infarction (AMI) in China. 11 12 5 Methods 13 14 6 In an observational study (China PEACE–Retrospective Study) of AMI care, we used 15 16 7 a 2-stage, random sampling strategy to create a nationally representative sample of 17 18 8 28,208 patientsFor with AMI peer at 162 Chinese review hospitals in 2001,only 2006, 2011, and 2015. 19 20 9 The main outcome is use of IV magnesium sulfate over time. 21 22 10 Results 23 24 11 We identified 24,418 patients admitted for AMI, without hypokalemia, in the four 25 26 12 study years. Over time, there was a significant initial decrease in IV magnesium 27 28 sulfate use, from 32.1% in 2001 to 17.1% in 2015 (p< .001 for trend). The decline 29 13 30 31 14 was greater in the Eastern (from 33.3% to 16.5%) and Western (from 34.8% to 32 33 15 17.2%) regions, as compared with the Central region (from 25.9% to 18.1%), with 34 35 16 little difference between rural and urban areas. The proportion of hospitals using IV 36 37 17 magnesium sulfate did not change over time (from 81.3% to 77.9%). The median http://bmjopen.bmj.com/ 38 39 18 odds ratios, representing hospital-level variation, were 6.03 in 2001, 3.86 in 2006, 40 41 19 4.26 in 2011, and 4.72 in 2015. IV magnesium sulfate use was associated with 42 43 20 cardiac arrest at admission and receipt of reperfusion therapy, but no hospital- 44 on September 25, 2021 by guest. Protected copyright. 45 21 specific characteristics. 46 47 22 Conclusions 48 49 50 23 Despite recommendations against its use, IV magnesium sulfate is used in about 1 in 51 52 24 6 patients with AMI in China. Our findings highlight the need for more efficient 53 54 25 mechanisms to stop using ineffective therapies to improve patients’ outcomes and 55 56 26 reduce medical waste. 57 58 27 59 60 28

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1 2 3 Clinical Trial Registration

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 URL: https://www.clinicaltrials.gov. Unique identifier: NCT01624883 6 7 3 Keywords 8 9 10 4 acute myocardial infarction, Magnesium Sulfate, quality of health care 11 12 5 13 14 6 15 16 7 Strengths and limitations of this study 17 18 8  This is theFor first large peer nationally review representative registryonly demonstrating IV 19 20 9 magnesium sulfate is still used in about 1 in 6 patients with AMI in China, 21 22 10 despite recommendations against its use since 2000s. 23 24 11  The study assessed the 15-year trend in the use of IV magnesium sulfate 25 26 12 among patient with AMI in China. 27 28 13  The study firstly reported both patients- and hospital-level resulted in the use 29 30 14 of IV magnesium sulfate use, which could provide more targeted information 31 32 15 for efficient mechanisms to stop using this ineffective therapy. 33 34 16  The study adopted standardized procedures for abstraction of medical 35 36 17 records that ensure the reliability of our results in describing the use pattern 37 http://bmjopen.bmj.com/ 38 18 of magnesium sulfate in the real world. 39 40 19  The very low prevalence of patients with some indications, such as 41 42 20 magnesium sulfate deficiency would have little influence on the reliability of 43 44 21 the results. 45 on September 25, 2021 by guest. Protected copyright. 46 22 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 INTRODUCTION

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 The history of intravenous (IV) magnesium sulfate use for acute myocardial infarction 6 7 3 (AMI) is convoluted. Once lauded in small, early trials as safe and highly effective,1-3 8 9 10 4 it was later demonstrated to be ineffective, and even harmful, in two large clinical 11 4 5 12 5 trials (MAGIC and ISIS-4) and in a subsequent meta-analysis. Beginning in the 13 14 6 early 2000s, AMI practice guidelines in the United States have specifically 15 16 7 recommended against its routine use (Class III, level of evidence: C).6 7 Similarly, 17 18 8 China publishedFor guidelines peer in 2001 recommendingreview against only the use of IV magnesium 19 20 9 sulfate in patients with AMI, except in the setting of hypomagnesemia or polymorphic 21 22 10 ventricular tachycardia.8 23 24 11 25 26 12 Although several studies have evaluated the introduction and uptake of new 27 28 therapies,9-11 few have examine de-adoption of ineffective therapy in clinical 29 13 30 12 31 14 practice. The de-adoption of therapy is particularly important because the situation 32 33 15 may involve greater resistance and barriers to discontinuing long-standing practices 34 35 16 than simply introducing new and promising therapies into practice.13 Characterizing 36 37 17 the use of magnesium sulfate for AMI in clinical practice offers an opportunity to http://bmjopen.bmj.com/ 38 39 18 assess the speed with which providers stop using a therapy when new evidence has 40 41 19 overturned prior dogma. 42 43 20 44 on September 25, 2021 by guest. Protected copyright. 45 21 Accordingly, our objectives were to assess the trends and variation of regional and 46 47 22 hospital-level use of IV magnesium sulfate among patient with AMI using data from 48 49 50 23 the China PEACE Retrospective AMI Study between 2001 and 2015. These data, 51 52 24 from a nationally representative network of hospitals throughout China, provided a 53 54 25 unique opportunity to examine the trend for discontinuing routine IV magnesium 55 56 26 sulfate over time and to describe the variations across hospitals in its discontinuation. 57 58 27 59 60 28

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1 2 3 METHODS

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 Design Overview 6 7 3 The design and methods of the China PEACE-Retrospective AMI Study have been 8

9 14 10 4 previously published. In addition to a nationally representative sample of patients 11 12 5 admitted for AMI in China during 2001, 2006, and 2011 created in the China PEACE- 13 14 6 Retrospective AMI Study, we also included a more recent sample of patients 15 16 7 admitted in 2015 using the same two-stage random sampling process. Briefly, in the 17 18 8 first stage, we identifiedFor hospitalspeer using review a simple random only sampling procedure within 19 20 9 5 economic-geographic regions: Eastern rural, Central rural, Western rural, Eastern 21 22 10 urban, and Central/Western urban. We stratified on both location and urban-rural 23 24 11 classifications because economic development and clinical capacities differed across 25 26 12 these categories. We sampled representative hospitals from 2011 to reflect current 27 28 practices and used the same hospitals for the 2006, 2001, and 2015 so as to 29 13 30 31 14 describe temporal trends. In the second stage, we sampled AMI cases from hospital 32 33 15 databases in 2001, 2006, 2011, and 2015 using random sampling procedures. 34 35 16 36 37 17 Trained personnel at the national coordinating centers abstracted data from the http://bmjopen.bmj.com/ 38 39 18 medical records using standardized data definitions. Data abstraction quality was 40 41 19 rigorously monitored by randomly auditing 5% of the medical records, in a process 42 43 20 that ensured that the overall variable accuracy exceeded 98%.14 We also obtained 44 on September 25, 2021 by guest. Protected copyright. 45 21 information on the organizational learning culture of hospital in 2013 through 46 47 22 questionnaires completed by the director and a physician of the Cardiology 48 49 15 50 23 Department in each participating hospital (see Appendix B). 51 52 24 53 54 25 The Ethics Committee at the National Center for Cardiovascular Diseases approved 55 56 26 the study. All collaborating hospitals either accepted central ethics approval or 57 58 27 obtained local ethics approval by their ethics committees. Given the retrospective 59 60 28 nature of the data and the lack of personal identifiers, patient-level consent was not

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1 2 3 required. The study was registered with ClinicalTrials.gov (NCT01624883).

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 6 7 3 Study Sample 8 9 10 4 Among the randomly sampled patients hospitalized for AMI in 2001, 2006, 2011, and 11 12 5 2015, only patients with a definite discharge diagnosis of AMI were included. We 13 14 6 were unable to exclude patients with hypomagnesemia, because magnesium levels 15 16 7 were not collected. However, we excluded patients with chart-documented 17 18 8 hypokalemia duringFor their peer hospitalization, review which could alsoonly represent an indication for 19 20 9 magnesium repletion. In hospital-level analysis, only hospitals with 10 or more cases 21 22 10 in a study year were included. 23 24 11 25 26 12 Variables 27 28 Receipt of IV magnesium sulfate was ascertained from the medical record. Patient- 29 13 30 31 14 level characteristics abstracted from the medical records included demographics 32 33 15 (age, gender), medical history (hypertension, diabetes, dyslipidemia, current 34 35 16 smoking, and history of myocardial infarction, coronary heart disease, ischemic 36 37 17 stroke, coronary artery bypass grafting (CABG), or primary coronary intervention http://bmjopen.bmj.com/ 38 39 18 (PCI)), clinical presentation (chest discomfort, heart rate, systolic blood pressure on 40 41 19 admission, and left bundle branch block on electrocardiogram), as well as in-hospital 42 43 20 complications (cardiac arrest, cardiogenic shock, and acute stroke) and year of 44 on September 25, 2021 by guest. Protected copyright. 45 21 hospitalization (2001, 2006, 2011, 2015). The outcomes included: 1) in-hospital 46 47 22 mortality or withdrawal from treatment due to a terminal status at discharge; and 2) 48 49 50 23 in-hospital composite of major complications (including death, withdrawal from 51 52 24 treatment, re-infarction, shock, ischemic stroke, or congestive heart failure 53 54 25 (Appendix). Hospital characteristics included teaching status, PCI capability, 55 56 26 economic geographic regions, and urban or rural location. 57 58 27 59 60 28 Organizational learning culture was measured with Learning Organization Survey

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1 2 3 (LOS-27, an abbreviated version of the original Garvin et al. Learning Organization

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 Survey).16 The LOS-27 consists of 27 questions, grouped into 7 domains of 6 7 3 organizational learning characteristics, including supportive learning environment, 8 9 10 4 time for reflection, leadership that reinforces learning, experimentation, training, 11 12 5 knowledge acquisition, and performance monitoring. 13 14 6 15 16 7 Statistical analysis 17 18 8 To examine theFor trends at peer both the population review and hospital only levels across different 19 20 9 study periods, p-values for trends were reported using the Cochran–Armitage test. 21 22 10 We described the hospital-level distribution of the IV magnesium sulfate use among 23 24 11 the hospitals with at least 10 patients with AMI in the study years. To further 25 26 12 understand the hospital-level variation in IV magnesium sulfate use, we quantified 27 28 inter-hospital variation using the median odds ratio (MOR), by constructing 29 13 30 31 14 generalized estimating equations in 2001, 2006, 2011, and 2015, respectively. MOR 32 33 15 represents the average (median) OR for receiving IV magnesium sulfate for 2 AMI 34 35 16 patients with similar clinical characteristics admitted to 2 randomly selected hospitals. 36 37 17 http://bmjopen.bmj.com/ 38 39 18 To understand the most current pattern in IV magnesium sulfate use, we constructed 40 41 19 multivariable models using the data from 2015, which also adopted generalized 42 43 20 estimating equations to account for the clustering of patients within hospitals. Factors 44 on September 25, 2021 by guest. Protected copyright. 45 21 were selected based on clinical judgment and literature review,10,11 including patient 46 47 and hospital characteristics. All covariates, except those with frequencies below 1%, 48 22 49 50 23 were included in the multivariable model. We transformed continuous variables (e.g. 51 52 24 age and heart rate) into categorical variables using clinically meaningful cut-off 53 54 25 values, and then created dummy variables. From the multivariable model in 2015, we 55 56 26 then computed risk-standardized rates for each hospital separately. The risk- 57 58 27 standardized rate was calculated as the ratio of observed to predicted outcomes, 59 60 28 multiplied by the overall unadjusted rate, a form of indirect standardization.

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1 2 3

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 To compare the outcomes between patients with and without IV magnesium sulfate, 6 7 3 we applied propensity score matching to adjust differences in observed 8 9 10 4 characteristics between them. We obtained the log odds of the probability that 11 12 5 patients received IV magnesium sulfate with modeling a function of all the variables 13 14 6 in Table1. Then we performed a one-to-one no replacement match between the two 15 16 7 groups based on the estimated propensity score. The no IV magnesium sulfate 17 18 8 patients was matchedFor if patientpeer had thereview closest score withonly a randomly selected IV 19 20 9 magnesium sulfate patient, and were considered eligible to match if the estimated 21 22 10 logit within 0.6 standard deviation of the selected IV magnesium sulfate patient. This 23 24 11 matching interval has been shown to eliminate approximately 90% of the bias in 25 26 12 observed confounders (Appendix).17 27 28 29 13 30 31 14 For the questionnaire with LOS-27 (Appendix), we analyzed the responses at the 32 33 15 hospital level by calculating the average of the 2 responses to each question. 34 35 16 Responses were categorized as positive if they were 5 on a 7-point scale or 4 on a 36 37 17 5-point scale. We then calculated the positive response rate at each hospital as the http://bmjopen.bmj.com/ 38 39 18 proportion of questions that had a positive response by the hospital, and 40 41 19 demonstrated the correlations between positive response rate and risk-standardize 42 43 20 rate of IV magnesium sulfate use in 2015, as well as the reduction in IV magnesium 44 45 on September 25, 2021 by guest. Protected copyright. 46 21 sulfate use from 2011 to 2015. 47 48 22 49 50 23 All comparisons were two-sided, with statistical significance defined as p less 51 52 24 than .05. Statistical analysis was done with SAS software, version 9.4, and R 53 54 25 software, version 3.3.1. 55 56 26 57 58 27 Patient and Public Involvement statement 59 60 28 Patients or public were not involved in the development of the study protocol.

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1 2 3 RESULTS

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 Study population 6 7 3 We identified 28,208 patients with AMI in 2001, 2006, 2011 and 2015 admitted to 8 9 10 4 162 hospitals. After excluding patients with hypokalemia (<3.5 mmol/L, n= 3,004), 11 12 5 24,418 patients remained, including 2,073 in 2001, 3,888 in 2006, 8,117 in 2011 and 13 14 6 10,340 in 2015 (Figure 1). In the study population, the average age was 65.1±12.7 15 16 7 years, 29.7% were female, almost three quarters had at least one cardiac risk factors 17 18 8 (hypertension, diabetes,For peerdyslipidemia review or smoking), and only about 10% had has a prior 19 20 9 myocardial infarction or ischemic stroke (Table 1). 21 22 10 23 24 25 11 Temporal trends and regional variations in IV magnesium sulfate use 26 27 12 Over time, there was a significant initial decrease in the use of IV magnesium sulfate, 28 29 13 from 32.1% (665) in 2001 to 18.4% (715) in 2006, 15.4% (1,251) in 2011 and 17.1% 30 31 14 (1,763) in 2015 (p< .001 for trend) (Figure 2). There was significant variation in the 32 33 15 temporal trends of use of IV magnesium sulfate across the five strata (p< .001 for 34 35 16 interaction). In general, the decline was greater in the Eastern region [16.8% (from 36 http://bmjopen.bmj.com/ 37 17 33.3% in 2001 to 16.5% in 2015), p< .001] and Western region [16.6% (from 34.8% 38 39 18 in 2001 to 17.2% in 2015), p< .001], compared with the Central regions [7.8% (from 40 41 19 25.9% in 2001 to 18.1% in 2015), p< .001]. There was a more modest difference 42 43 44 20 between rural areas [16.3% (from 31.6% to 15.3%), p< .001] than in urban areas 45 on September 25, 2021 by guest. Protected copyright. 46 21 [13.9% (from 32.4% to 18.5%), p< .001]. No significant association was found 47 48 22 between the positive response rate of LOS-27 in 2013 and the hospital-level 49 50 23 reduction in IV magnesium sulfate use from 2011 to 2015 (R2=0.011, p= .237) 51 52 24 (Appendix C). 53 54 25 55 56 26 Hospital-level distributions in IV magnesium sulfate use 57 58 27 We examined hospital-level rates of IV magnesium sulfate use among hospitals with 59 60

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1 2 3 10 or more cases per year, and observed a downward trend in the median, from

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 17.4% in 2001, 9.1% in 2006, 8.0% in 2011 to 10.7% in 2015 (Figure 3). However, 6 7 3 the proportion of hospitals still using magnesium sulfate were 81.3% in 2001, 84.8% 8 9 10 4 in 2006, 76.6% in 2011, and 77.9% in 2015, with no significant decline (p for trend 11 12 5 = .26). Even in 2015, a quarter of hospitals had rates of IV magnesium sulfate use 13 14 6 exceeding 25%. The MORs (95% CI) of each year characterized similar degrees of 15 16 7 hospital-level variation (6.03 (3.93-8.52) in 2001, 3.86 (3.00-.4.77) in 2006, 4.26 17 18 8 (3.38-5.20) in 2011,For and peer4.72 (3.70-5.83) review in 2015). only 19 20 9 21 22 10 Patient and hospital characteristics associated with IV magnesium sulfate use 23 24 11 In univariate analysis, patients receiving IV magnesium sulfate were more likely to 25 26 12 not have diabetes, dyslipidemia or a prior revascularization, were more likely to have 27 28 had a prior ischemic stroke or cardiac arrest at presentation. They were more likely 29 13 30 31 14 to receive reperfusion therapy, be at urban hospital, or be in Central or Western 32 33 15 regions (Table 1). In the multivariable model, presence of cardiac arrest at admission 34 35 16 (OR 3.41, 95% CI 2.2-5.26, P< .001) and receipt of reperfusion therapy (1.64 (1.38- 36 37 17 1.94) for fibrinolytic therapy, 1.68 (1.44-1.97) for primary PCI, both P< .0001) were http://bmjopen.bmj.com/ 38 39 18 positively associated with IV magnesium sulfate use. No significant difference was 40 41 19 identified across the teaching status, economic geographic region and rural/urban of 42 43 20 hospitals (Table 1). The risk-standardized rate of IV magnesium sulfate use in 2015 44 on September 25, 2021 by guest. Protected copyright. 45 21 was not associated with the positive response rate of LOS-27 (R2=0.027, p= .04) 46 47 22 (Appendix C). 48 49 50 23 51 52 24 In-hospital outcomes of patients with and without IV magnesium sulfate use 53 54 25 In the patients treated with IV magnesium sulfate, the crude rates of in-hospital death 55 56 26 (7.5% vs. 6.4%) (Figure 4), in-hospital death or treatment withdraw (10.8% vs. 57 58 27 9.5%), and in-hospital composite of major complications (22.0% vs. 17.6%) were 59 60 28 higher than patients without IV magnesium sulfate therapy (P< .01 for all). After

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1 2 3 adjusted for hospital characteristics, patient risk profiles and reperfusion therapies,

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 using propensity score matching, the in-hospital death rates were not significantly 6 7 3 different between the treated and non-treated patients (OR 1.13, 95% CI 0.96-1.33, 8 9 10 4 P= .15). However, the patients treated with IV magnesium sulfate had still higher risk 11 12 5 for in-hospital death or treatment withdraw (OR 1.19, 95% CI 1.04-1.37, P= .01), and 13 14 6 in-hospital composite of major complications (OR 1.35, 95% CI 1.21-1.50, P< .001). 15 16 7 17 18 8 DISCUSSION For peer review only 19 20 9 In this large nationally representative study, we found that despite an initial decline in 21 22 10 the use of IV magnesium sulfate for patients with AMI in China after 2001, about 1 in 23 24 11 6 patients continued to be treated with it through 2015. Furthermore, there was 25 26 12 substantial variation in the use of IV magnesium sulfate use across hospitals. No 27 28 hospital characteristics were associated with IV magnesium sulfate use after 29 13 30 31 14 adjusting for patient factors. including cardiac arrest and use of reperfusion therapy 32 33 15 during hospitalization. 34 35 16 36 37 17 Our study is the first, to our knowledge, to characterize the rate of de-adoption of http://bmjopen.bmj.com/ 38 39 18 magnesium sulfate in patients with AMI in China. The only study on the use of 40 41 19 magnesium sulfate to treat AMI, which was based on data from the National Registry 42 43 20 of Myocardial Infarction (NRMI-2) in the United States, found that the use rate of 44 on September 25, 2021 by guest. Protected copyright. 45 21 magnesium sulfate in patients within first 24 hours after AMI was 5.1% in 2001 – 5 46 47 22 years after the US guideline recommended against the use of magnesium sulfate.18 48 49 50 23 In contrast in 2015, three-fold more Chinese patients with AMI were receiving 51 52 24 magnesium sulfate. This is congruent with a survey among cardiologists in 2012, 53 54 25 where over one fifth reported that they were routinely using magnesium sulfate in 55 56 26 patients with ACS.19 57 58 27 59 60 28 Several patient characteristics were identified to be associated with the use of IV

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1 2 3 magnesium sulfate for AMI. It was plausible that the presence of cardiac arrest or

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 reperfusion therapy may spur some physicians to use magnesium sulfate to prevent 6 7 3 arrhythmias, according to prior studies in both China and other countries.1 6 20-23 8 9 10 4 These explanations, even though not recommended by the guidelines, highlighted 11 12 5 the gaps in physicians’ practice and highlights the needs for targeted education in the 13 14 6 future. 15 16 7 17 18 8 The hospital-levelFor and regional peer variations review in IV magnesium only sulfate highlights the 19 20 9 marked variability with which different hospitals adopted new evidence about the lack 21 22 10 of benefit from IV magnesium sulfate use. On the one hand, magnesium sulfate use 23 24 11 in 2015 was neither associated with hospital-specific characteristics, nor different 25 26 12 across geographic or socio-economic regions. On the other hand, the regional 27 28 variation in de-adoption of magnesium sulfate during the 15-year period seemed not 29 13 30 31 14 directly related to the regional socio-economic development status that might be 32 33 15 assumed to affect the resources available for acquiring and implementing guideline 34 35 16 recommendation. Moreover, no evidence connects organizational learning culture 36 37 17 with high performance, even much has been observed in studies of US hospitals.24 http://bmjopen.bmj.com/ 38 39 18 Given our findings, more research is needed to better understand current practice 40 41 19 patterns that cause some hospitals to still use ineffective therapies. 42 43 20 44 on September 25, 2021 by guest. Protected copyright. 45 21 Our findings raise several questions about the dissemination and implementation of 46 47 22 evidence and guidelines in China, particularly regarding education for physicians 48 49 50 23 when long-standing therapies are demonstrated to be non-beneficial, and need to be 51 52 24 de-adopted. We hypothesized that several factors may explain why the rate of 53 54 25 magnesium sulfate use has remained relatively high in China. First, few actions have 55 56 26 been taken to disseminate guidelines – after China published the guideline against IV 57 58 27 magnesium sulfate for AMI in 2001,8 the textbook used in all Chinese medical 59 60 28 colleges had not stopped recommending IV magnesium sulfate use in patients with

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1 2 3 AMI until 2009.25 Second, China’s hospital system is short for mechanisms to

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 facilitate the implementation of guideline recommendations, and systematic 6 7 3 approaches for monitoring the performance of hospitals and physicians in following 8

9 26 10 4 the guidelines are lacking in China. 11 12 5 13 14 6 The successful de-adoption of non-beneficial or potentially harmful therapies for 15 16 7 corresponding disease, which could reduce costs and potentially prevent 17 18 8 complications, requiresFor morepeer than increased review efforts from only the part of guideline 19 20 9 developers.12 After the dissemination of the guideline, more complicated issues need 21 22 10 to be addressed, including how to develop tools reminding and alerting physicians 23 24 11 when non-recommended therapies are ordered, how to establish a system to report 25 26 12 feedback periodically on the appropriateness of treatment by practitioners and 27 28 hospitals, how to design an accountability-oriented mechanism to prohibit ineffective 29 13 30 31 14 regimen being prescribed, etc. These issues could only be properly addressed 32 33 15 through collaborations with researchers, educators, policymakers and other 34 35 16 stakeholders.27 28 36 37 17 http://bmjopen.bmj.com/ 38 39 18 This study has several limitations that warrant consideration. First, we could not 40 41 19 exclude patients with some indications, such as magnesium sulfate deficiency and 42 43 20 episodes of Torsade de pointes. However, we estimate that this number is relatively 44 on September 25, 2021 by guest. Protected copyright. 45 21 small given previous reports documenting a low prevalence of magnesium sulfate 46 47 deficits in AMI patients.29 30 Second, we did not have the ability to prospectively ask 48 22 49 50 23 clinicians why they were prescribing IV magnesium sulfate, which limited our 51 52 24 capability to gain better understanding of the use pattern and influencing factors. 53 54 25 Third, our data were acquired retrospectively through medical record abstraction. 55 56 26 Thus, the quality of our data depends on the accuracy and completeness of prior 57 58 27 documentation and abstraction. Nevertheless, the standardized procedures for 59 60 28 abstraction of medical records ensure the reliability of our results in describing the

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1 2 3 use pattern of magnesium sulfate in the real world. Finally, we analyzed the data at

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 the hospital level and were not able to determine whether the observed patterns 6 7 3 were due to only a few physicians, or were common throughout a hospital’s staff. 8 9 10 4 11 12 5 In conclusion, the de-adoption of magnesium sulfate for patients with AMI is 13 14 6 suboptimal, moreover, the decrease of rate was slowing down recently, steady at an 15 16 7 unacceptably high level. Our findings highlight the need for more efficient 17 18 8 mechanisms to Fortranslate peer evidence-based review therapies into only clinical practice in China to 19 20 9 improve patients’ outcomes and reduce medical waste. 21 22 10 23 24 11 ACKNOWLEDGMENTS 25 26 12 We appreciate the multiple contributions made by study teams at National Clinical 27 28 Research Center of Cardiovascular Diseases and Yale-New Haven Hospital Center 29 13 30 31 14 for Outcomes Research and Evaluation in study design and operations, particularly 32 33 15 the data collection by Yi Pi, Jiamin Liu, Wuhanbilige Hundei, Haibo Zhang, Lihua 34 35 16 Zhang, Wenchi Guan, Xiaofang Yan, Yuan Yu, Xiqian Huo, Xin Zheng, and Yuanlin 36 37 17 Guo. We appreciate the editing by Aoxi Tian. We are grateful for the support http://bmjopen.bmj.com/ 38 39 18 provided by the Chinese government. 40 41 19 42 43 20 CONTRIBUTORS 44 on September 25, 2021 by guest. Protected copyright. 45 21 XL, JL and HMK conceived the China PEACE study and take responsibility for all 46 47 22 aspects of it. XW, XD, JL, FAM, JAS, JL, HMK and XL designed the study. XW and 48 49 50 23 XD wrote the first draft of the article, with further contributions from HY, EB, ND, JAS, 51 52 24 FAM, JL, WG, HMK and XL. SH, YG and XB did statistical analysis. XL had full 53 54 25 access to all the data in the study and take responsibility for the integrity of the data 55 56 26 and the accuracy of the data analysis. All authors interpreted data and approved the 57 58 27 final version of the article. 59 60 28

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1 2 3 DISCLOSURES

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 There are no relevant conflicts of interest. 6 7 3 8 9 10 4 FUNDING 11 12 5 This project was partly supported by the National Key Research and Development 13 14 6 Program (2017YFC1310803, 2017YFC1310801，2015BAI12B01) from the Ministry 15 16 7 of Science and Technology of China, the Major Public Health Service Project from 17 18 8 the Ministry of FinanceFor andpeer National Healthreview and Family only Planning Commission of 19 20 9 China, the 111 Project from the Ministry of Education of China (B16005). Dr. 21 22 10 Krumholz is supported by grant U01 HL105270-05 (Center for Cardiovascular 23 24 25 11 Outcomes Research at Yale University). The sponsors had no role in the conduct of 26 27 12 the study; in the collection, management, analysis, and interpretation of the data; or 28 29 13 in the preparation or approval of the manuscript. 30 31 14 32 33 15 DATA SHARING STATEMENT 34 35 Extra data is available by emailing [email protected]. 36 16 37 17 http://bmjopen.bmj.com/ 38 39 18 40 41 19 42 43 20 REFERENCE 44 45 on September 25, 2021 by guest. Protected copyright. 46 21 1. Horner SM. Efficacy of intravenous magnesium in acute myocardial infarction 47 22 in reducing arrhythmias and mortality. Meta-analysis of magnesium in 48 49 23 acute myocardial infarction. Circulation 1992;86(3):774-9. [published 50 51 24 Online First: 1992/09/01] 52 53 25 2. Teo KK, Yusuf S, Collins R, et al. Effects of intravenous magnesium in suspected 54 55 26 acute myocardial infarction: overview of randomised trials. BMJ 56 27 1991;303(6816):1499-503. [published Online First: 1991/12/14] 57 58 28 3. Thogersen AM, Johnson O, Wester PO. Effects of magnesium infusion on 59 60 29 thrombolytic and non-thrombolytic treated patients with acute myocardial

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1 2 3 4 1 infarction. Int J Cardiol 1993;39(1):13-22. [published Online First: BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 2 1993/04/01] 6 7 3 4. ISIS-4: a randomised factorial trial assessing early oral captopril, oral 8 9 4 mononitrate, and intravenous magnesium sulphate in 58,050 patients with 10 11 5 suspected acute myocardial infarction. ISIS-4 (Fourth International Study 12 6 of Infarct Survival) Collaborative Group. Lancet 1995;345(8951):669-85. 13 14 7 [published Online First: 1995/03/18] 15 16 8 5. Early administration of intravenous magnesium to high-risk patients with acute 17 18 9 myocardialFor infarction peer in the review Magnesium in only Coronaries (MAGIC) Trial: a 19 10 randomised controlled trial. Lancet 2002;360(9341):1189-96. [published 20 21 11 Online First: 2002/10/29] 22 23 12 6. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the 24 25 13 management of patients with ST-elevation myocardial infarction-- 26 27 14 executive summary: a report of the American College of 28 15 Cardiology/American Heart Association Task Force on Practice Guidelines 29 30 16 (Writing Committee to Revise the 1999 Guidelines for the Management of 31 32 17 Patients With Acute Myocardial Infarction). Circulation 2004;110(5):588- 33 34 18 636. doi: 10.1161/01.cir.0000134791.68010.fa [published Online First: 35 19 2004/08/04] 36 37 20 7. Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the http://bmjopen.bmj.com/ 38 39 21 management of patients with acute myocardial infarction. A report of the 40 41 22 American College of Cardiology/American Heart Association Task Force on 42 23 Practice Guidelines (Committee on Management of Acute Myocardial 43 44 24 Infarction). J Am Coll Cardiol 1996;28(5):1328-428. [published Online First: 45 on September 25, 2021 by guest. Protected copyright. 46 25 1996/11/01] 47 48 26 8. China Society of Cardiology of Chinese Medical Association EBoCJoC. Guideline 49 27 for diagnosis and treatment of patients with acute myocardial infarction. 50 51 28 Chinese Circulation Journal 2001;16(6):407-22. 52 53 29 9. Gambassi G, Forman DE, Lapane KL, et al. Management of heart failure among 54 55 30 very old persons living in long-term care: has the voice of trials spread? The 56 31 SAGE Study Group. Am Heart J 2000;139(1 Pt 1):85-93. [published Online 57 58 32 First: 2000/01/05] 59 60 33 10. Kim N, Gross C, Curtis J, et al. The impact of clinical trials on the use of hormone

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1 2 3 4 1 replacement therapy. A population-based study. J Gen Intern Med BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 2 2005;20(11):1026-31. doi: JGI221 [pii] 6 7 3 10.1111/j.1525-1497.2005.0221.x [published Online First: 2005/11/26] 8 9 4 11. Stafford RS, Furberg CD, Finkelstein SN, et al. Impact of clinical trial results on 10 11 5 national trends in alpha-blocker prescribing, 1996-2002. JAMA 12 6 2004;291(1):54-62. doi: 10.1001/jama.291.1.54 [published Online First: 13 14 7 2004/01/08] 15 16 8 12. Hauptman PJ, Schnitzler MA, Swindle J, et al. Use of nesiritide before and after 17 18 9 publicationsFor suggesting peer drug-relatedreview risks only in patients with acute 19 10 decompensated heart failure. JAMA 2006;296(15):1877-84. doi: 20 21 11 10.1001/jama.296.15.1877 [published Online First: 2006/10/19] 22 23 12 13. Niven DJ, Rubenfeld GD, Kramer AA, et al. Effect of published scientific 24 25 13 evidence on glycemic control in adult intensive care units. JAMA Intern Med 26 27 14 2015;175(5):801-9. doi: 10.1001/jamainternmed.2015.0157 [published 28 15 Online First: 2015/03/17] 29 30 16 14. Dharmarajan K, Li J, Li X, et al. The China Patient-Centered Evaluative 31 32 17 Assessment of Cardiac Events (China PEACE) retrospective study of acute 33 34 18 myocardial infarction: study design. Circulation Cardiovascular quality and 35 19 outcomes 2013;6(6):732-40. doi: 10.1161/circoutcomes.113.000441 36 37 20 [published Online First: 2013/11/14] http://bmjopen.bmj.com/ 38 39 21 15. Yin ES, Downing NS, Li X, et al. Organizational culture in cardiovascular care in 40 41 22 Chinese hospitals: a descriptive cross-sectional study. Bmc Health Services 42 23 Research 2015;15(1):569. 43 44 24 16. Singer SJ, Moore SC, Meterko M, et al. Development of a short-form Learning 45 on September 25, 2021 by guest. Protected copyright. 46 25 Organization Survey: the LOS-27. Med Care Res Rev 2012;69(4):432-59. doi: 47 48 26 10.1177/1077558712448135 49 27 17. Xing SG, Rosenbaum PR. Comparison of Multivariate Matching Methods: 50 51 28 Structures, Distances, and Algorithms. Journal of Computational & 52 53 29 Graphical Statistics 1993;2(4):405-20. 54 55 30 18. Ziegelstein RC, Hilbe JM, French WJ, et al. Magnesium use in the treatment of 56 31 acute myocardial infarction in the United States (observations from the 57 58 32 Second National Registry of Myocardial Infarction). Am J Cardiol 59 60 33 2001;87(1):7-10. [published Online First: 2001/01/04]

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1 2 3 4 1 19. Yiping Chen LJ, Qiuli Zhang, Xiaoshuai Wei, Xi Li, Margaret Smith, Zhengming BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 2 Chen. Doctor-reported hospital management of acute coronary syndrome 6 7 3 in China: A nationwide survey of 1029 hospitals in 30 provinces. World 8 9 4 Journal of Cardiovascular Diseases 2012;2:168-76. doi: 10 11 5 10.4236/wjcd.2012.23029 Published Online July 2012 12 6 20. Abraham AS, Rosenmann D, Kramer M, et al. Magnesium in the prevention of 13 14 7 lethal arrhythmias in acute myocardial infarction. Arch Intern Med 15 16 8 1987;147(4):753-5. [published Online First: 1987/04/01] 17 18 9 21. Rapaport E.For Guidelines peer for the acutereview coronary syndromes.only Current cardiology 19 10 reports 2001;3(4):289-98. [published Online First: 2001/06/19] 20 21 11 22. Raghu C, Peddeswara Rao P, Seshagiri Rao D. Protective effect of intravenous 22 23 12 magnesium in acute myocardial infarction following thrombolytic therapy. 24 25 13 Int J Cardiol 1999;71(3):209-15. [published Online First: 2000/01/15] 26 27 14 23. Zhou H, Sun M. Suppresion of thrombolysis-induced reperfusion arrhythmias 28 15 in acute myocardial infarction by magnesium sulfate. Journal of Clinical 29 30 16 Cardiology 2000;16(4):156-58. 31 32 17 24. Bradley EH, Curry LA, Spatz ES, et al. Hospital strategies for reducing risk- 33 34 18 standardized mortality rates in acute myocardial infarction. Ann Intern 35 19 Med 2012;156(9):618-26. doi: 10.7326/0003-4819-156-9-201205010- 36 37 20 00003 http://bmjopen.bmj.com/ 38 39 21 25. Lu Z, Zhong N. Internal Medicine (The seventh edition). Beijing: People's 40 41 22 Medical Publishing House 2009. 42 23 26. Jiang L, Krumholz HM, Li X, et al. Achieving best outcomes for patients with 43 44 24 cardiovascular disease in China by enhancing the quality of medical care 45 on September 25, 2021 by guest. Protected copyright. 46 25 and establishing a learning health-care system. Lancet 47 48 26 2015;386(10002):1493-505. 49 27 27. Carrese JA, Malek J, Watson K, et al. The essential role of medical ethics 50 51 28 education in achieving professionalism: the Romanell Report. Academic 52 53 29 medicine : journal of the Association of American Medical Colleges 54 55 30 2015;90(6):744-52. doi: 10.1097/acm.0000000000000715 [published 56 31 Online First: 2015/04/18] 57 58 32 28. Grimshaw J, Eccles M, Tetroe J. Implementing clinical guidelines: current 59 60 33 evidence and future implications. The Journal of continuing education in the

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1 2 3 4 1 health professions 2004;24 Suppl 1:S31-7. doi: 10.1002/chp.1340240506 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 2 [published Online First: 2005/02/17] 6 7 3 29. Kafka H, Langevin L, Armstrong PW. Serum magnesium and potassium in acute 8 9 4 myocardial infarction. Influence on ventricular arrhythmias. Arch Intern 10 11 5 Med 1987;147(3):465-9. [published Online First: 1987/03/01] 12 6 30. Romano TJ. Serum magnesium levels may not indicate low tissue magnesium 13 14 7 levels. Arch Intern Med 1997;157(4):460. [published Online First: 15 16 8 1997/02/24] 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 Table 1. Baseline characteristics of using IV magnesium sulfate 4 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 Characteristics Overall Use N(%) Non-Use(%) P value 7 Patient characteristics 8 Age .234 9 10 <55 5262(21.5) 938(21.3) 4324(21.6) 11 55-64 5821(23.8) 1072(24.4) 4749(23.7) 12 13 65-74 6989(28.6) 1290(29.4) 5699(28.5) 14 >=75 6346(26) 1094(24.9) 5252(26.2) 15 16 Gender .144 17 Female 7257(29.7) 1346(30.6) 5911(29.5) 18 For peer review only Male 17161(70.3) 3048(69.4) 14113(70.5) 19 20 Hypertension 12551(51.4) 2247(51.1) 10304(51.5) .7 21 Diabetes 4758(19.5) 768(17.5) 3990(19.9) <.001 22 23 Dyslipidemia 1588(6.5) 235(5.3) 1353(6.8) <.001 24 Currently smoking 8084(33.1) 1496(34) 6588(32.9) .144 25 26 Prior ischemic stroke 2706(11.1) 546(12.4) 2160(10.8) .002 27 Prior myocardial infarction 2504(10.3) 416(9.5) 2088(10.4) .057 28 29 Prior CABG/PCI 713(2.9) 104(2.4) 609(3) .016 30 Chest discomfort 22211(91) 4021(91.5) 18190(90.8) .161 31 Left branch block at presentation 342(1.4) 65(1.5) 277(1.4) .624 32 33 Cardiac arrest at presentation 271(1.1) 81(1.8) 190(0.9) <.001 34 Cardiogenic shock at 35 36 presentation 1436(5.9) 279(6.3) 1157(5.8) .145 http://bmjopen.bmj.com/ 37 Acute stroke at presentation 530(2.2) 77(1.8) 453(2.3) .036 38 39 Heart rate at presentation, bpm .052 40 <50 1019(4.2) 177(4) 842(4.2) 41 50-110 21760(89.1) 3886(88.4) 17874(89.3) 42 43 >110 1639(6.7) 331(7.5) 1308(6.5) 44 SBP at presentation, mmHg .004 45 on September 25, 2021 by guest. Protected copyright. 46 <120 8181(33.5) 1565(35.6) 6616(33) 47 120-139 7534(30.9) 1299(29.6) 6235(31.1) 48 49 140-159 5041(20.6) 913(20.8) 4128(20.6) 50 >=160 3662(15) 617(14) 3045(15.2) 51 Reperfusion therapies <.001 52 53 No reperfusion 18720(76.7) 3130(71.2) 15590(77.9) 54 Fibrinolytic therapy 3136(12.8) 746(17) 2390(11.9) 55 56 Primary PCI 2562(10.5) 518(11.8) 2044(10.2) 57 Hospital characteristics 58 59 Teaching hospital 19081(78.1) 3462(78.8) 15619(78) .252 60 Hospital level .075

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1 2 3

Secondary or lower 9045(37) 1576(35.9) 7469(37.3) BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 Tertiary hospital 15373(63) 2818(64.1) 12555(62.7) 6 Economic geographic region .01 7 8 Eastern 13614(55.8) 2360(53.7) 11254(56.2) 9 Central 5886(24.1) 1115(25.4) 4771(23.8) 10 11 Western 4918(20.1) 919(20.9) 3999(20) 12 Urban/Rural .003 13 Rural 10064(41.2) 1724(39.2) 8340(41.7) 14 15 Urban 14354(58.8) 2670(60.8) 11684(58.3) 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 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 Figure 1. Flowchart of study cohort 4 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 7 Figure 2. Trends of intravenous magnesium sulfate therapy in 2001, 2006, 2011 8 9 10 and 2015 in five economic-geographic regions. 11 12 13 Figure 3. IV magnesium sulfate use in 2001, 2006, 2011 and 2015 among all 14 15 hospitals. 16 17 18 For peer review only 19 Figure 4. In-hospital outcomes between patients with and without IV 20 21 magnesium sulfate. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 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 Figure 1 26 27 338x190mm (96 x 96 DPI) 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 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. 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 Figure 2 29 30 179x119mm (300 x 300 DPI) 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 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 75 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. 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 Figure 3 40 127x127mm (300 x 300 DPI) 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 Page 29 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from

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1 2 3 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 APPENDIX 5 6 7 A. China PEACE-Retrospective AMI Study Site Investigators by Hospital 8 9 Aba Tibetan and Qiang Autonomous Prefecture People's Hospital, ShipingWeng, ShuyingXie; 10 11 Affiliated Hospital of Guiyang Medical College, Lirong Wu, Jiulin Chen; Affiliated Hospital of Hainan 12 13 Medical College, Tianfa Li, Jun Wang; Affiliated Zhongshan Hospital of Dalian University, Qin Yu, 14 15 Xiaofei Li; Alxa League Central Hospital, Zhong Li, ShiguoHao, Yuzhen Zhang, Xuemei Wu; 16 17 Baiquan County People's Hospital, Yachen Zhang, Zhifeng Liu; Biyang People's Hospital, Zhongxin 18 For peer review only 19 Wang, HaoJia; Bortala Mongol Autonomous Prefecture People's Hospital, Bayin Bate, BadengQiqige; 20 21 Changda Hospital Of Anshan, Xiang Jin, Ting Cai; Chengwu County People's Hospital, Fengqin Liu, 22 23 Dayong Xu; Chenxi County People's Hospital, Xuejin He, Shui Yang; Chongren County People's 24 25 Hospital, Chun Yuan, Jiping Wang; County People's Hospital of Jinning, LihuaGu, Lin Li, Shijiao 26 27 Chen; Dalian Municipal Central Hospital, YongchaoZhi, Lili Sun; Dao County People's Hospital, 28 29 Shengcheng Zhou, Lingjiao Jin; Daofu County People's Hospital, Yong Leng, Liangchuan Zhang, 30 31 Tianyun Deng; Dingyuan County People's Hospital of Anhui Province, Yuanjin Wang, Wenhua Zhang, 32 33 34 Xinmin Ma; Dongyang People's Hospital, Weimin Li, Liang Lu, Xuan Ge; Dulong and Nu 35 36 Autonomous County People's Hospital of Gongshan, Xiaoping Wu, Yanming He; Dunhua City 37 http://bmjopen.bmj.com/ 38 Hospital of Jilin Province, FanjuMeng, Jia Li; Fenghuang County People's Hospital, Dexi Liao, 39 40 Guangyong Liu, Wen Qin; Fengshan County People’s Hospital, Wen Long, Xiangwen Chen; Fourth 41 42 Hospital of Baotou City, Baohong Zhang, Yonghou Yin, Bin Tian; Fourth People's Hospital of Zigong 43 44 City, Yong Yi, Chaoyong Wu; Fugu County People's Hospital of Shaanxi Province, Baoqi Liu, Zhihui 45 on September 25, 2021 by guest. Protected copyright. 46 Zhao, Haiming Li; Fujian Provincial Hospital, YansongGuo, Xinjing Chen; Fuling Center Hospital of 47 48 Chongqing City, Liquan Xiang, Lin Ning; Gannan County People's Hospital, Mei Chen, Xin Jin, 49 50 Guiling Li; General Hospital of the Yangtze River Shipping, Xiuqi Li, Xing’an Wu; Gongcheng Yao 51 52 Autonomous County People's Hospital, Congjun Tan, Mingfang Feng, Meili Wang; Guangchang 53 54 County People's Hospital, Liangfa Wen, Xiang Fu, QunxingXie; Guilin People's Hospital, Wei Zhang, 55 56 Yanni Zhuang, Hua Lu;Guiping People's Hospital, Jiaqian Lu, Yu Huang; Haerbin 242 Hospital, Yin 57 58 Zhou, Qiuling Hu; Haiyan People's Hospital, Chunhui Xiao, Xiaoli Hu; Heling Ge Er County People's 59 60 Hospital, Yongshuan Wu, Qiuli Wang; Helong Municipal People's Hospital, Youlin Xu, Xuefei Yu;

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1 2 3 4 Henan Provincial People's Hospital, Chuanyu Gao, Jianhong Zhang, You Zhang; Heze Municipal BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 Hospital, WentangNiu, Xiaolei Ma, Yong Wang; HGKY Group Company General Hospital, Xiaowen 7 8 Pan, Yanlong Liu; Hua Xin HospitalFirst Hospital of Tsinghua University, Lifu Miao, Yanping Yin, 9 10 Zhiying Zhang; Huairen People's Hospital, Shutang Feng; Huayin People's Hospital, Aiping Wang, 11 12 Jiangli Zhang, Feipeng Li; Huaying People's Hospital , Hong Wang; Hunchun Hospital, Lijun Yu, 13 14 Xinxin Zhao; Huizhou Municipal Central Hospital, Yuansheng Shen, Zhiming Li, Lizhen He; Hunan 15 16 Province Mawangdui Hospital, ZhiyiRong, Wei Luo; Ji'an Municipal Central People's hospital, 17 18 Xueqiao Wang; JianghuaFor Yao peer Autonomous Countyreview People's Hospital, only Rongjun Wan, Jianglin Tang, 19 20 Guanghan Wu; Jiangsu Haimen People's Hospital, Jie Wu, Bin Xu; Jiangxi Provincial People's 21 22 Hospital, Qing Huang, Xiaohe Wu; Jiangzi County People's Hospital, Sang Ge, Pian Pu, PingcuoDuoji; 23 24 Jilin Province People's Hospital, Hui Dai, Yuming Du, Wei Guo; Jilin Integrated Traditional Chinese 25 26 & Western Medicine Hospital, Jilin Province, Jianping Shi; Jinghai County Hospital, Peihua Zhao, 27 28 Jingsheng Sun; Jingxi County People's Hospital, Hongxiang Li, Wen Liang; Jingxing County Hospital, 29 30 Zhiwen Dong, Zhenhai Zhao; Jingzhou Central Hospital, Xin Li, Qin Xu; Jiuquan City People’s 31 32 Hospital, Yaofeng Yuan, Zhirong Li; Jixi People's Hospital of The Jixi Municipal People's Hospital 33 34 Medical Group, Jinbo Gao; Jize County Hospital, Qiu’eGuo; Kangbao County People's Hospital, 35 36 Ruiqing Zhao, Guangjun Song; Keshiketengqi Hospital of Chifeng City, Lize Wang, Haiyun Song; 37 http://bmjopen.bmj.com/ 38 Lanping Bai and Pumi Autonomous County People's Hospital, Jinwen He, Jinming He; Laoting 39 40 County Hospital, Keyong Shang, Changjiang Liu, Kuituan Xi; Liaoyang Central Hospital, Rihui Liu, 41 42 Peng Guo; Liaoyuan Central Hospital, ChaoyangGuo, Xiangjun Liu, Rujun Zhao, Zeyong Yu; Lindian 43 44 County Hospital, Wenzhou Li, Xudong Jing, Huanling Wang; Linxiang People's Hospital, Xiyuan 45 on September 25, 2021 by guest. Protected copyright. 46 Zhao, Chao Zhang, Long Chen; Liujiang County People's Hospital, Meifa Wei, Yan Liu, Shengde 47 48 Chen; Longyan First Hospital, Kaihong Chen, Yong Fang, Ying Liao; Luancheng County Hospital, 49 50 Junli Wang, Tianyu Liu, Suzhe Cheng; Lucheng People's Hospital, Yunke Zhou, XiaoxiaNiu, Huifang 51 52 Cao; Luchuan County People's Hospital, Zebin Feng, Min Feng; Luxi County People's Hospital, 53 54 FeilongDuan, Haiming Yi; Luyi County People's Hospital, Yuanxun Xu, AnranGuo; Macheng People's 55 56 Hospital, Xianshun Zhou, HongzhuanCai, Peng Zheng; Mengcheng First People's Hospital, 57 58 GaofengGuo; MenglianLahudaiwa autonomous counties People's Hospital, Xiang Li; Min County 59 60

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1 2 3 4 People's Hospital, MinwuBao, Yuhong Liu; Nanjing First Hospital, Shaoliang Chen, HaiboJia, BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 Hongjuan Peng; Nan’an Hospital, Duanping Dai, Shaoxiong Hong; Nantong Third People's Hospital, 7 8 Song Chen, Dongya Zhang, Ying Wang; Nanyang Central Hospital, Yudong Li, Jianbu Gao, 9 10 Shouzhong Yang; Ningwu County People's Hospital, Junhu An; Peking University People's Hospital, 11 12 Chenyang Shen, Yunfeng Liu; Peking University Shenzhen Hospital, Chun Wu, Huan Qu, Saiyong 13 14 Chen; People's Hospital of Jingyu, Yuhui Lin, Dehai Jiao; People's Hospital of Yueqing City, Manhong 15 16 Wang, Qiu Wang; Pianguan County People's Hospital, YingliangXue, Ruijun Zhang; Puding County 17 18 People's Hospital, ChengFor Yuan, peer Lei Wu; Qinghai review Red Cross Hospital, only Jianqing Zhang, Chunmei Wei, 19 20 Yanmei Shen; Qinshui County People's Hospital, Hehua Zhang, Hongmei Pan, Yong Gao; Qinyang 21 22 People's Hospital, Xiaowen Ma, Yanli Liang, Tianbiao Wang; Queshan County People's Hospital, 23 24 Daguo Zhao; Quzhou People's Hospital, XiaomingTu, Zhenyan Gao; Rongjiang County People's 25 26 Hospital, Fangning Wang, Qiang Yang; Rudong County People's Hospital, Xiaoping Kang, Jianbin 27 28 Fang, Dongmei Liu; Ruyang County People's Hospital, Chengning Shen, Mengfei Li; Shangluo 29 30 Central Hospital, Yingmin Guan, Wenfeng Wang, Ting Xiao; ShangqiuChangzheng People's Hospital, 31 32 Qian Wang; Shaoyang County People's Hospital, Fengyun Jiang, Kaiyou Wu; Shengsi People's 33 34 Hospital, Songguo Wang; Shenyang Weikang Hospital, Xujie Fu, Shu Zhang,Lifang Gao; 35 36 ShougangShuicheng Iron & Steel (Group) Co·, Ltd. General Hospital, Min Zhang, Kai Fu, 37 http://bmjopen.bmj.com/ 38 XiaojingDuan; Shuangshan Hospital Of Anshan, Rui Xiao, Ruixia Wu, Bin Li; Siziwang County 39 40 People's Hospital, Hongtu Zhang, Yuerong Ma, Zhonghui Cao; SunanYugur Autonomous County 41 42 People's Hospital, Zhansheng Ba, Wanhai Fu; Taizhou Hospital of Zhejiang Province, Jianjun Jiang, 43 44 YafeiMi, Weiwei Zhou; The Affiliated Hospital of Beihua University, Feng Sun, Qi Zhang, Shiyu 45 on September 25, 2021 by guest. Protected copyright. 46 Zheng; The Fifth People's Hospital of Dalian, Jing Zhang, Yang Zhong; The First Affiliated Hospital 47 48 of Hebei North University, Fangjiang Li, Xiaoyuan Wang; The First Affiliated Hospital of Henan 49 50 University of Science & Technology, Pingshuan Dong, Laijing Du, Wei Liu; The First Affiliated 51 52 Hospital Of Jia Mu Si University, Zhaofa He, Meihua Jin; The First Hospital of Fuzhou City, Ting 53 54 Jiang, Zhuoyan Chen; The First Hospital of Xi’an, Manli Cheng, YuqiangJi; The First People's 55 56 Hospital of Danzhou, Youhua Zhou, Jvyuan Li; The First People's Hospital of Guangzhou, Yizhi Pan, 57 58 Jian Liu; The First People's Hospital of Guangyuan, Tianxun Wang, Ping Yang; The Fourth People's 59 60

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1 2 3 4 Hospital of Shangqiu Shi, Guiyu Huang, JianjunPan,QingliangCai,Qianying Wang; The General BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 Hospital of Yongzhou, Hunan Province, MingliLv; The people's hospital of Wuchuan, Yuanming Yi, 7 8 Xuelian Deng; The People's Hospital of Yuanling, Wenhua Chen, RongCai; The People's Hospital of 9 10 Zhijiang City, Bing Zhang; The Second Affiliated Hospital of Harbin Medical University, Bo Yu, 11 12 Yousheng Xu, Zhengqiu Wang; The Second Affiliated Hospital of Kunming Medical University, Jun 13 14 Shu, Ge Zhang, Kai Li; The Second Central Hospital of Baoding City, Guang Ma, PuxiaSuo; The 15 16 Second People's Hospital of Liaoyuan City, Aimin Zhang, Yongfen Kang; Tianjin Medical University 17 18 General Hospital, ZhengFor Wan,Yuemin peer Sun, Boreview Bian; Tibet Autonomous only Region People's Hospital, 19 20 Xuejun Hu, DawaCiren; Tongchuan Mining Bureau Central Hospital, GuojiongJia, Jieli Pan; 21 22 Tongliang County People's Hospital, Guofu Li, Hongliang Zhang, Longliang Zhan; Tongliao City 23 24 Horqin District First People's Hospital, Junping Fang, Xinli Yu; Ulanqab Central Hospital, Dacheng 25 26 Wang, Dajun Liu, Xinhong Cao; Wencheng County People's Hospital, Yi Tian, 27 28 HaishengZhu,Wanchuan Liu; Wuhai People's Hospital, Zhaohai Zhou, Lei Shi; Wuhu Second People's 29 30 Hospital, Wuwang Fang, Manxin Chen; Wulate County People's 31 32 Hospital, ,FuqinHan,JianyeFu,Yunmei Wang; Wuqiang County People's Hospital, Binglu Liu, 33 34 YanliangZhang,Xiupin Yuan; Wuyishan Municipal Hospital, Qingfei Lin, Yun Chen; Xiangtan County 35 36 People's Hospital, Yuliang Zhu, ZhiqiangCai; Xing County People's Hospital, Xingping Li, LirongAo; 37 http://bmjopen.bmj.com/ 38 Xingshan County People's Hospital, Shubing Wu, Hui Zhang; Xinmi First People's Hospital, Fusheng 39 40 Zhao, Guangming Yang; Xinshao County People's Hospital, Renfei Liu, Wenwei Ai; Xiuwu County 41 42 People's Hospital, JianbaoChang,Haijie Zhao; Xuanhan County People's Hospital, Qijun Ran, Xuan 43 44 Ma; Xupu County People's Hospital, Shijun Jiang, Xiaochun Shu; Yanggao County People's Hospital, 45 on September 25, 2021 by guest. Protected copyright. 46 Zhiru Peng, Yan Han; Yanqing County Hospital, Jianbin Wang, Li Yang; Ying County People's 47 48 Hospital, Yu Shen, Xingcun Shang; Yitong Manchu Autonomous County First People's Hospital, 49 50 Haifeng Wang; Yongxing County People's Hospital, Hongyan Li, Zhisong Liao, Yang Cao; Yuanzhou 51 52 District People's Hospital of Guyuan City, Xiaoping Gao, MeiyingCai, Lining You; Yuncheng Central 53 54 Hospital, Xuexin Li, Shuqin Li, Yingjia Li; Yunlong County People's Hospital, Jianxun Yang, Song 55 56 Ai, Jianfei Ma; Yuyao People's Hospital, Lailin Deng; ZhangjiachuanHui Autonomous County First 57 58 People's Hospital, Keyu Wang, Shitang Gao, Jian Guan; Zhouning County Hospital, Banghua He, 59 60

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1 2 3 4 Youyi Lu; Zhuoni County People's Hospital, Weirong Yang, Hong Li; Zhuozi County People's BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 Hospital, Zhizhong Zhang, Xiaohong Chi; Zuoyun County People's Hospital, Ru Duan, Guangli Wang. 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 B. China PEACE hospital survey: design, conduction, and materials BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 Participants 7 8 In the collaborative network, we invited the principal investigator and the coordinator of each hospital 9 10 to participate in the survey. The definitions of the roles were established during the planning phase of 11 12 the China PEACE-Retrospective AMI Study: typically, the director of the Cardiology Department or 13 14 Internal Medicine Department at each hospital served as the principal investigator, and the China 15 16 PEACE study coordinator was most often a physician selected by the principal investigator. 17 18 Survey design For peer review only 19 20 We organized the survey in 4 sections: personal information of the respondent (part A); general 21 22 information about the hospital and the department in charge of AMI care (part B); information about 23 24 hospital practices relating to the diagnosis and treatment of cardiovascular heart disease (part C); and 25 26 organizational learning characteristics and quality improvement for AMI care (part D). Organizational 27 28 learning culture was measured using questions from the Short-Form Learning Organization Survey 29 30 (LOS-27) and the Survival after AMI (SAMI) study. 31 32 The survey was written in English and translated into Chinese. To ensure accuracy, a double translation 33 34 was conducted in which the survey was translated into Chinese and then back into English 35 36 independently by 2 bilingual Chinese medical researchers. Modifications were made to the Chinese 37 http://bmjopen.bmj.com/ 38 translation accordingly. Participants were informed at the start of the survey that their responses would 39 40 be used to study institutional characteristics and medical care patterns. 41 42 Survey conduction 43 44 The survey was piloted using a convenience sample of 6 hospitals with percutaneous coronary 45 on September 25, 2021 by guest. Protected copyright. 46 intervention capability. The principal investigators were invited to participate in the pilot, and one 47 48 study coordinator also volunteered to participate. The responses of the 6 principal investigators (3 via 49 50 in-person interviews and 3 via self-administered paper-based survey) and 1 study coordinator (via self- 51 52 administered paper-based survey) were collected. The cognitive interviewing methodology, in which 53 54 individual in-person interviews were conducted with each pilot participant, was used to assess 55 56 understanding of the pilot survey. For paper-based pilot surveys, cognitive interviewing consisted of 57 58 retrospective (post-survey) probes; for in-person interviews, concurrent (during survey) probes allowed 59 60

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1 2 3 4 participants to provide survey feedback in real-time. Based on the experience from the pilot, minor BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 revisions were made to clarify the meaning of certain questions, and the sequence of questions was 7 8 modified to improve logic and flow. No questions were removed or added. All data from the pilot 9 10 testing were included in the final data set. 11 12 The survey was available in 2 forms: web-based e-survey, in which each participant was able to log in 13 14 with a unique password to a website where the survey was hosted, and PDF-based survey, in which 15 16 subjects digitally marked their answers in PDF files and returned the files via email. We applied 2 17 18 methods to ensure Forthe quality peerof the responses. review We checked the response only data for completeness, either 19 20 by automatic verification (web-based) or by manual check by our staff (PDF-based), and on the basis 21 22 of logic. For the web-based e-survey submissions, we used automatic logic check and verification 23 24 while subjects were responding to the survey, and recorded total time spent on the survey. For the 25 26 PDF-based survey submissions, we conducted a manual logic check, focusing on whether subjects 27 28 correctly skipped inapplicable questions as indicated by the instructions in other parts of the survey. In 29 30 cases of missing or illogical (e.g., questions incorrectly skipped or completed) data for PDF-based 31 32 surveys, we contacted respondents by email and/or phone, informed them of which questions needed to 33 34 be resolved, and asked them to resubmit the survey with the necessary changes. 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 Survey questionnaires BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 A. Personal information 6 7 A.1 Gender: 8 ○ Male ○ Female 9 Education 10 A.2 ○ Junior high school 11 ○ Senior high school (technical school or technical secondary school) 12 13 ○ College (junior college) 14 ○ Postgraduate 15 A.3 Clinical job title: 16 ○ Consultant ○ Attendant ○ Resident ○ Nurse ○ Other, please specify: ___ 17 18 A.4 Senior administrativeFor position peer in hospital: review only 19 ○ No ○ Yes, please specify: ___ 20 You have been working in the department for __ years. 21 A.5 22 23 B. General Information of the hospital and the department 24 25 Instructions: This section focuses on characteristics of your hospital and department. For all 26 questions, please reflect upon them during the 1-year period from 1/1/2011 to 12/31/2011 (for 27 some of them, please consider 1/1/2001 to 12/31/2001, and 1/1/2006 to 12/31/2006, as specified). 28 Even some questions in this section might be somewhat hard to answer immediately, especially 29 those about the characteristics of your hospital or department in 2001 and 2006. Please try best 30 to find the answer - as accurate as possible - to every applicable question. 31 32 B.1 Affiliated hospital of medical college: 33 ○ No ○ Yes, please specify the name of the college: ______[Skip to B3] 34 Teaching hospital of medical college: 35 B.2 ○ No ○ Yes, please specify the name of the college: ______36 37 Total No. in your department http://bmjopen.bmj.com/ 38 In 2001 In 2006 In 2011 39 40 B.3 Beds 41 Consultants 42 B.4 43 B.5 Attendants 44

Residents on September 25, 2021 by guest. Protected copyright. 45 B.6 46 B.7 Nurses 47 B.8 Is there any other department in your hospital providing inpatient treatment for AMI? 48 ○ No ○ Yes, please specify the name of the department: ______49 50 B.9 Coronary Care Unit (CCU) in hospital? 51 ○ No ○ Yes, please specify the No. of beds: ______52 Cath lab in hospital? 53 B.10 ○ No [Skip to B12] ○ Yes, please specify when started: ______54 55 B.11 How many qualified cardiac interventionalist there are in your hospital: ______○ unknown 56 Could CABG be performed in hospital? 57 B.12 58 ○ No ○ Yes, please specify the No. of cases in 2011: ______59 60

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1 2 3 Independent emergency department? B.13 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 ○ No ○ Yes, please specify the No. of cardiologists in charge in emergency department normally: 5 ______6 7 B.14 Formal GCP training of clinical staff in your department? 8 ○ No ○ Yes ○ Unknown 9 Have your apartment participated in international clinical trials? 10 B.15 11 ○ No ○ Yes, please specify the names of the trials: ______○ Unknown 12 B.16 SFDA certified site for CVD drug trials? 13 ○ No ○ Yes ○ Unknown 14 15 B.17 Existence of Ethics Committee in hospital? 16 ○ No ○ Yes ○ Unknown 17 Total No. in your hospital 18 For peer review only 19 In 2001 In 2006 In 2011 20 B.18 Patients with stroke 21 22 B.19 Patients with ischemic stroke 23 B.20 Patients with hemorrhagic stroke 24 25 B.21 Independent neurology department? 26 ○ No ○ Yes, please specify the No. of beds in the department: ______27 B.22 Carotid endarterectomy performed in hospital? 28 ○ No ○ Yes, please specify when started: ______○ Unknown 29 30 B.23 Carotid stenting performed in hospital? 31 ○ No ○ Yes, please specify when started: ______○ Unknown 32 The average cost of the following items in your hospital 33 34 Items Cost, ￥ 35 Biochemical test, including glucose, lipid, liver function, renal function, CRP or hsCRP 36 B.24 http://bmjopen.bmj.com/ 37 B.25 Coagulation function test 38 BNP or NT-proBNP 39 B.26 40 B.27 Stress test 41 42 43 B.28 UCG 44 on September 25, 2021 by guest. Protected copyright. 45 B.29 Cardiac CT 46 47 B.30 48 Carotid US 49 50 51 C. Diagnosis and treatment for CHD 52 Instructions: This section focuses on hospital processes and care of patients with AMI. For all 53 questions, please reflect upon them during the 1-year period from 1/1/2011 to 12/31/2011. 54 55 C.1 Routine diagnostic test of CK for ACS patients after admission? 56 57 ○ No ○ Yes, please specify the average time delay in reporting results: ______○ Unknown 58 59 60

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C.2 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Routine diagnostic test of CK-MB for ACS patients after admission? 5 6 ○ No ○ Yes, please specify the average time delay in reporting results: ______○ Unknown 7 8 C.3 Routine diagnostic test of troponin for ACS patients after admission? 9 10 ○ No ○ Yes, please specify the average time delay in reporting results: ______○ Unknown 11 12 C.4 13 Are patients who are stable after PCI admitted to an intensive care unit? SAMI-Q25 14 15 ○ Always ○ Usually ○ Sometimes ○ Rarely ○ Unknown 16 17 C.5 Did your emergency department use a uniform protocol to care for patients who arrived to the 18 For peer review only 19 emergency department with STEMI? SAMI-Q26 20 21 ○ No ○ Yes ○ Unknown 22 23 C.6 Did your emergency department use a uniform protocol to care for patients who arrived to the 24 25 emergency department with Unstable Angina/NSTEMI? SAMI-Q27 26 27 ○ No ○ Yes ○ Unknown 28 29 30 C.7 Did your hospital use simulations (i.e., trial exercises, dry-runs) to practice any of the following AMI 31 32 care processes? [Check all that apply] SAMI-Q28 33 34 □ Door-to-balloon or door-to-drug protocols 35 36 □ Chest pain in hospitalized patients 37 http://bmjopen.bmj.com/ 38 □ Inpatient codes (e.g., cardiac arrest, respiratory failure) 39 40 □ None above 41 42 □ Unknown 43 44

C.8 To which patient care unit were patients who were stable with Unstable Angina/NSTEMI most likely on September 25, 2021 by guest. Protected copyright. 45 46 admitted? SAMI-Q29 47 48 ○ CCU ○ ICU ○ Step-down unit ○ Designated chest pain/telemetry/cardiology floor 49 50 51 ○ General medicine floor ○ We did not have a routine method of assigning beds for patients with 52 53 Unstable Angina/NSTEMI ○ Unknown 54 55 C.9 Did all, or nearly all, patients with AMI have a cardiologist as their primary attending physician? 56 57 SAMI-Q30 58 59 ○ No ○ Yes [Skip to C11] ○ Unknown 60

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C.10 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Were cardiology consults required for all patients with AMI? SAMI-Q30a 5 6 ○ No ○ Yes ○ Unknown 7 8 C.11 In the intensive care unit, who was primarily responsible for the care of patients with AMI? [Check 9 10 all that apply] SAMI-Q31 11 12 □ Critical care physicians (i.e., intensivists) 13 14 □ Cardiologist/s based exclusively in the unit 15 16 □ Other cardiologists 17 18 □ Other, pleaseFor specify: ______peer review only 19 20 □ Unknown 21 22 C.12 Electronic medical record? 23 ○ No [Skip to C14] ○ Yes, please specify when started: ______○ Unknown 24 25 C.13 Did your hospital use an electronic medical record (EMR) in the following areas? [Check all 26 27 that apply] SAMI-Q34 28 29 □ Emergency department 30 31 □ Inpatient floors 32 33 □ Critical care units 34 35 □ Affiliated ambulatory offices/clinics 36 37 http://bmjopen.bmj.com/ □ None above 38 39 40 C.14 On the inpatient floors, did your hospital have the following electronic capabilities? [Check all that 41 42 apply] SAMI-Q35 43 44 □ Computerized assisted physician order entry 45 on September 25, 2021 by guest. Protected copyright. 46 □ Computer prompts to alert user to potential drug-drug interactions or allergies 47 48 □ Computer prompts to alert user to potential errors in dosing and information 49 50 □ Computer prompts to alert user to medication order expiration 51 52 □ Computer prompts to improve adherence to core measures for AMI care (e.g., beta-blocker use) 53 54 □ None above 55 56 57 58 59 60

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C.15 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 In the emergency department, were prior ECG’s electronically available at the time of care? SAMI- 5 6 Q36 7 8 ○ No ○ Yes ○ Unknown 9 10 C.16 Did physicians regularly use explicit protocols or clinical pathways for patients with AMI? SAMI- 11 12 Q37 13 14 ○ No ○ Yes ○ Unknown 15 16 C.17 17 Did clinicians on the inpatient care units regularly use order sets (either paper-based or electronic) for 18 For peer review only 19 patients with STEMI? SAMI-Q38 20 21 ○ No ○ Yes ○ Unknown 22 23 C.18 Did clinicians on the inpatient care units regularly use order sets (either paper-based or electronic) for 24 25 with Unstable Angina/NSTEMI? SAMI-Q39 26 27 ○ No ○ Yes ○ Unknown 28 29 C.19 30 Which of the following types of physicians were at the hospital 24-hours/day and 7-days/week? 31 32 [Check all that apply] SAMI-Q42 33 34 □ Critical care physicians (i.e., intensivists) 35 36 □ Non-interventional cardiologists 37 http://bmjopen.bmj.com/ 38 □ Interventional cardiologists 39 40 □ Cardiology fellows (including non-interventional and interventional) 41 42 □ Hospitalists 43 44 □ None above 45 on September 25, 2021 by guest. Protected copyright. 46 C.20 Are there any protocols used to guide nurses on when to call the attending cardiologist for patients 47 48 with AMI? SAMI-Q43 49 50 ○ No ○ Yes ○ Unknown 51 52 C.21 53 Patients with acute coronary syndrome who arrived by Emergency medical service (ambulance): 54 55 ○ None [Skip to C25] ○ 1–25% ○ 26–50% ○ 51–75% ○ 76-100% ○ 56 57 Unknown 58 59 60

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C.22 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Emergency medical service routinely gives pre-alert calls? 5 6 ○ No ○ Yes ○ Unknown 7 8 C.23 Patients with acute coronary syndrome who undergo ECG en route to hospital: 9 10 ○ None ○ 1–25% ○ 26–50% ○ 51–75% ○ 76-100% ○ Unknown 11 12 C.24 13 Emergency medical service routinely tell your hospital the results of ECG? 14 15 ○ No ○ Yes ○ Unknown 16 17 C.25 Formal training of triage staff for assessing acute coronary syndrome? 18 For peer review only 19 ○ No ○ Yes ○ Unknown 20 21 C.26 Dedicated space in triage area for immediate ECG? 22 23 ○ No ○ Yes ○ Unknown 24 25 26 C.27 Written criteria for immediate ECG in emergency department? 27 28 ○ No ○ Yes ○ Unknown 29 30 C.28 Expected interval between patients’ arriving and ECG? 31 32 ○ ≤5 min ○ 6–20 min ○ >20 min ○ No expected time ○ Unknown 33 34 C.29 35 Dedicated ECG technicians in emergency department? 36 37 ○ No ○ Yes, only some shifts ○ Yes, always ○ Unknown http://bmjopen.bmj.com/ 38 39 C.30 Thrombolysis for AMI patients in hospital? 40 ○ No [Skip to C38] ○ Yes, please specify when started: _____ 41 42 43 C.31 Does your hospital have a set protocol to identify eligible patients for thrombolysis? 44

○ No ○ Yes ○ Unknown on September 25, 2021 by guest. Protected copyright. 45 46 C.32 Does your hospital have a set protocol to assess contraindications of thrombolysis? 47 48 ○ No ○ Yes ○ Unknown 49 50 51 C.33 Who makes the decision about thrombolysis in your hospital? 52 53 ○ Emergency medicine physician alone 54 55 ○ Emergency medicine physician with a cardiac consultation 56 57 ○ Only Cardiologist 58 59 ○ Unknown 60

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C.34 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 In your hospital, where do patients with AMI receive thrombolysis? 5 6 ○ In the emergency department 7 8 ○ In the cardiology department (or general medicine department) 9 10 ○ In the ICU or CCU 11 12 ○ Unknown 13 14 C.35 Where are the thrombolytic medicines stored and prepared? 15 16 ○ Stored and prepared in the department where thrombolysis is done 17 18 ○ PreparedFor in the department peer where review thrombolysis is done, only but stored in another location 19 20 ○ Stored and prepared in some location other than the department where thrombolysis is done 21 22 ○ Unknown 23 24 25 C.36 Informed Consent before thrombolysis? 26 27 ○ Not necessary 28 29 ○ Only orally obtained informed consent is needed 30 31 ○ One written informed consent form is needed 32 33 ○ More than one written informed consent form is needed 34 35 ○ Unknown 36 http://bmjopen.bmj.com/ 37 C.37 Prepayment before thrombolysis? 38 39 ○ No 40 41 ○ Yes, please specify the average amount approximately: ___ (“-1” if unknown) 42 43 ○ Unknown 44 45 on September 25, 2021 by guest. Protected copyright. 46 C.38 Primary PCI was performed in your hospital for STEMI patients? 47 48 ○ No [Skip to C60] ○ Yes, please specify when started: ___ 49 50 C.39 Activation of catheterization laboratory on weekdays? 51 52 ○ Emergency medicine physician with cardiologist 53 54 ○ Cardiologist alone 55 56 ○ Emergency medicine physician alone 57 58 ○ Unknown 59 60

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C.40 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Activation of catheterization laboratory at night and on weekends? 5 6 ○ Emergency medicine physician with cardiologist 7 8 ○ Cardiologist alone 9 10 ○ Emergency medicine physician alone 11 12 ○ Unknown 13 14 C.41 Process for activating catheterization team? 15 16 ○ After communicating with the emergency department, interventional cardiologist activates 17 18 catheterizationFor laboratory peer by calling review staff or a central page only operator 19 20 ○ Emergency department makes at least two calls: one to the interventional cardiologist and 21 22 another to a central page operator, who pages catheterization laboratory staff 23 24 ○ Emergency department makes a single call to a central page operator, who then pages 25 26 interventional cardiologist and catheterization laboratory staff 27 28 ○ No standard approach 29 30 ○ Other 31 32 ○ Unknown 33 34 35 C.42 Activation of on-call staff for catheterization laboratory? 36 37 ○ Page operator is not used http://bmjopen.bmj.com/ 38 39 ○ Page operator is used; confirmation of page receipt is required 40 41 ○ Page operator is used; no confirmation of page receipt is required 42 43 ○ No standard approach 44 45 ○ Unknown on September 25, 2021 by guest. Protected copyright. 46 47 C.43 First physician notified after STEMI diagnosis in emergency department? 48 49 ○ Cardiologist ○ Interventional cardiologist ○ Patient’s primary care physician ○ 50 51 Other or variable ○ Unknown 52 53 54 C.44 Laboratory and radiographic results are needed to activate catheterization laboratory? 55 56 ○ Yes ○ No ○ No standard approach ○ Unknown 57 58 59 60

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C.45 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Process after emergency medical service transmits ECG results? 5 6 ○ Emergency department waits for patient to arrive at hospital to determine whether 7 8 catheterization laboratory should be activated 9 10 ○ Emergency department contacts cardiologist while the patient is en route to determine whether 11 12 catheterization laboratory should be activated 13 14 ○ Emergency department activates catheterization laboratory while the patient is still en route to 15 16 the hospital 17 18 ○ No standardFor approach peer or variable reviewapproach only 19 20 ○ Not applicable because ECG data not transmitted en route 21 22 ○ Not applicable because ECG never performed en route 23 24 ○ Unknown 25 26 C.46 Expected interval between page and arrival of staff in catheterization laboratory? 27 28 ○ ≤20 min ○ 21–30 min ○ >30 min ○ No expected time ○ Unknown 29 30 31 C.47 Expected interval between page and arrival of interventional cardiologist? 32 33 ○ ≤20 min ○ 21–30 min ○ >30 min ○ No expected time ○ Unknown 34 35 C.48 Someone is always available to transport patients from emergency department to catheterization 36 http://bmjopen.bmj.com/ 37 laboratory? 38 39 ○ No ○ Yes ○ Unknown 40 41 C.49 42 Initiation of patient transport from emergency department to catheterization laboratory? 43 44 ○ After catheterization laboratory notifies emergency department it is ready 45 on September 25, 2021 by guest. Protected copyright. 46 ○ A set interval after the decision is made regarding PCI 47 48 ○ No standard approach 49 50 ○ Other approach 51 52 ○ Unknown 53 54 55 56 57 58 59 60

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C.50 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Minimum number of nurses and technicians required in catheterization laboratory before patient 5 6 is transported from emergency department? 7 8 ○ Interventional cardiologist must be present 9 10 ○ Interventional cardiologist may not be present but need presence of 1 staff person 11 12 ○ Interventional cardiologist may not be present but need presence of 2-4 staff person 13 14 ○ No set number 15 16 ○ Unknown 17 18 C.51 Elective catheterizationFor peer cases rescheduled review for emergency only PCI? 19 20 ○ Yes ○ No ○ It depends ○ Unknown 21 22 C.52 23 If interventionalist is present, number of staff required to begin PCI? 24 25 ○ 1 ○ 2 ○ 3 ○ 4 ○ Unknown 26 27 C.53 Catheterization laboratory is left so that next PCI can begin promptly? 28 29 ○ Yes ○ No ○ No standard policy ○ Unknown 30 31 C.54 32 Cardiology fellows participate in performing PCI? 33 34 ○ No ○ Yes ○ Unknown 35 36 C.55 Staff in critical care area are routinely cross-trained to cover catheterization laboratory? 37 http://bmjopen.bmj.com/ 38 ○ No ○ Yes ○ Unknown 39 40 C.56 Location of catheterization laboratory? 41 42 ○ Elevator required to travel from emergency department 43 44

○ Same floor as emergency department on September 25, 2021 by guest. Protected copyright. 45 46 47 C.57 An attending cardiologist is always at the hospital? 48 49 ○ No ○ Yes ○ Unknown 50 51 52 53 54 55 56 57 58 59 60

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C.58 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Informed Consent before primary PCI? 5 6 ○ Not necessary 7 8 ○ Only orally obtained informed consent is needed 9 10 ○ One written informed consent form is needed 11 12 ○ More than one written informed consent form is needed 13 14 ○ Unknown 15 16 C.59 Prepayment before primary PCI? 17 18 ○ No For peer review only 19 20 ○ Yes, please specify the average amount approximately ___ (“-1” if unknown) 21 22 ○ Unknown 23 24 25 C.60 Does your hospital measure the following time intervals? [Check all that apply] 26 27 □ Door to ECG 28 29 □ Door to needle 30 31 □ Door to balloon 32 33 □ None above 34 35 □ Unknown 36 http://bmjopen.bmj.com/ 37 C.61 Do your hospital feedback the time intervals to someone? [Check all that apply] 38 39 □ No 40 41 □ Yes, to physician staff involved in the care 42 43 □ Yes, to nursing staff involved in the care 44 45 on September 25, 2021 by guest. Protected copyright. □ Yes, to pharmacy staff involved in the care 46 47 □ Yes, to other staff involved in the care 48 49 □ Unknown 50 51 52 53 54 55 56 57 58 59 60

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C.62 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Do your hospital report the analyze results about the time intervals regularly? [Check all that apply] 5 6 □ No 7 8 □ Yes, to departments involved in the care (the emergency department, the cardiology department) 9 10 □ Yes, to other department in your hospital 11 12 □ Yes, to other institutions outside your hospital 13 14 □ Unknown 15 16 17 D. Organizational learning characteristics 18 For peer review only 19 Instructions: This section focuses on the organizational learning and measurements to improve 20 AMI care, including supportive environment and leadership, experimentation and training, 21 knowledge acquisition, reflection and performance monitoring, etc. Please draw on your own 22 experiences in your current role working with clinical staff and administration. For all questions, 23 please reflect upon them during the 1-year period from 1/1/2011 to 12/31/2011. 24 Although some questions in this section look similar, there are differences between them and you 25 should treat each one as a separate question. The best approach is to answer each question fairly 26 quickly. That is, don’t try to count up the number of times you felt a particular way, but rather 27 indicate the alternative that seems most reasonable. 28 29 The definition of “workgroup” below is the department, unit, ward, or group caring AMI 30 patients that you are working at. 31 This section adopts 7-point (from highly inaccurate to highly accurate). If you think the options 32 are difficult to understand or distinguish, please grade the accuracy here using actual numbers, 33 while 1 is the lowest (highly inaccurate), 7 is the highest (highly accurate), then choose the 34 corresponding option. 35 36 D.1 In this workgroup, people value new ideas. 37 http://bmjopen.bmj.com/ 38 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 39 40 highly accurate 41 42 D.2 43 Clinicians are encouraged to creatively solve problems related to AMI care processes. (60) 44 45 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always on September 25, 2021 by guest. Protected copyright. 46 47 D.3 Innovative ideas about AMI care are shared widely in the hospital. (61) 48 49 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 50 51 D.4 Differences in opinions are welcomed in this workgroup. 52 53 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 54 55 highly accurate 56 57 58 59 60

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D.5 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 In this workgroup, people are open to alternative ways of getting work done. 5 6 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 7 8 highly accurate 9 10 D.6 People in this workgroup are eager to share information about what doesn’t work as well as to share 11 12 information about what does work. 13 14 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 15 16 highly accurate 17 18 D.7 For peer review only 19 This workgroup frequently compares its performance to: Best-in-class organizations. 20 21 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 22 23 highly accurate 24 25 D.8 This workgroup frequently compares its performance to: Other similar workgroups. 26 27 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 28 29 highly accurate 30 31 D.9 32 This workgroup consistently collects information on technological trends. 33 34 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 35 36 highly accurate 37 http://bmjopen.bmj.com/ 38 D.10 If you make a mistake in this workgroup, it is often held against you. (Among clinicians taking care of 39 40 patients with AMI, there is a tendency to blame individuals for errors in patient care). (66) 41 42 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 43 44

D.11 Clinicians caring for patients with AMI are easily able to address problems and tough issues with their on September 25, 2021 by guest. Protected copyright. 45 46 department heads/chiefs. (56) 47 48 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 49 50 51 D.12 Department heads/chiefs are easily able to address problems and tough issues with senior level 52 53 administration.(57) 54 55 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 56 57 D.13 Nurses are comfortable checking with physicians if they have concerns about patient care.(65) 58 59 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 60

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D.14 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Clinicians involved in the care of patients with AMI value each others’ skills and talents (e.g., 5 6 physicians value nurses’ skills and talents and vice-versa).(58) 7 8 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 9 10 D.15 Clinicians involved in the care of patients with AMI avoid sharing responsibility for medical errors. ○ 11 12 Never ○ Rarely ○ Sometimes ○ Usually ○ Always. (59) 13 14 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 15 16 D.16 17 Were physicians explicitly encouraged to disclose medical errors to patients or their family members? 18 For peer review only 19 (7) 20 21 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 22 23 D.17 This workgroup engages in productive conflict and debate during discussions. 24 25 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 26 27 highly accurate 28 29 D.18 30 In this workgroup, we frequently identify and discuss underlying assumptions that might affect key 31 32 decisions. 33 34 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 35 36 highly accurate 37 http://bmjopen.bmj.com/ 38 D.19 The hospital has the resources and information it needs to reduce 30-day mortality rates in patients 39 40 with AMI. (51) 41 42 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 43 44

D.20 Senior-level administration is supportive of efforts to improve AMI care. (52) on September 25, 2021 by guest. Protected copyright. 45 46 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 47 48 49 D.21 There is simply no time for reflection in this workgroup. 50 51 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 52 53 highly accurate 54 55 D.22 In this workgroup, people are too busy to invest time in improvement. 56 57 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 58 59 highly accurate 60

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D.23 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 My manager(s) establish(es) forums for and provide(s) time and resources for identifying problems 5 6 and organizational challenges. 7 8 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 9 10 highly accurate 11 12 D.24 My manager(s) establish(es) forums for and provide(s) time and resources for reflecting and improving 13 14 on past performance. 15 16 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 17 18 highly accurateFor peer review only 19 20 D.25 21 My manager(s) listen(s) attentively. 22 23 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 24 25 highly accurate 26 27 D.26 My manager(s) invite(s) input from others in discussions. 28 29 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 30 31 highly accurate 32 33 D.27 34 This workgroup experiments frequently with new product/service offerings. 35 36 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 37 http://bmjopen.bmj.com/ 38 highly accurate 39 40 D.28 This workgroup experiments frequently with new ways of working. 41 42 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 43 44 highly accurate 45 on September 25, 2021 by guest. Protected copyright. 46 D.29 This workgroup frequently employs pilot projects or simulations when trying our new ideas. 47 48 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 49 50 51 highly accurate 52 53 D.30 This workgroup has a formal process for conducting and evaluating experiments or new ideas. 54 55 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 56 57 highly accurate 58 59 60

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D.31 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Experienced employees in this workgroup receive training when new initiatives are launched. 5 6 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 7 8 highly accurate 9 10 D.32 Experienced employees in this workgroup receive training when shifting to a new position. 11 12 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 13 14 highly accurate 15 16 D.33 17 Newly hired employees in this workgroup receive adequate training. 18 For peer review only 19 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 20 21 highly accurate 22 23 D.34 Did your hospital provide training to EMS providers about AMI care? (17) 24 25 ○ Yes, about monthly 26 27 ○ Yes, about quarterly 28 29 ○ Yes, about annually 30 31 ○ Yes, other: ______32 33 ○ No 34 35 ○ Unknown 36 37 http://bmjopen.bmj.com/ D.35 38 This workgroup has forums for meeting with and learning from: Experts from outside the organization. 39 40 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 41 42 highly accurate 43 44 D.36 This workgroup has forums for meeting with and learning from: Experts from other 45 on September 25, 2021 by guest. Protected copyright. 46 departments/teams/divisions. 47 48 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 49 50 highly accurate 51 52 D.37 53 This workgroup has forums for meeting with and learning from: Customers/clients. 54 55 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 56 57 highly accurate 58 59 60

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D.38 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 This workgroup regularly conducts post-audits, after-action reviews, and debriefings. 5 6 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate ○ 7 8 highly accurate 9 10 D.39 Did your hospital have regular ‘morbidity and mortality’ conferences (or another educational session) 11 12 for discussing individual cases involving patients with AMI? (5) 13 14 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 15 16 D.40 17 Did your hospital review the deaths of patients with AMI? (4a) 18 For peer review only 19 ○ No, we did not review these cases (go to D44) 20 21 ○ Yes, we reviewed only deaths with potential quality issues (i.e., unexpected deaths) 22 23 ○ Yes, we reviewed all deaths 24 25 ○ Other, please specify: ______26 27 ○ Unknown 28 29 D.41 Did your hospital have a designated person or group to review the deaths of patients with AMI 30 31 (i.e., on an individual case level) that occurred during hospitalization? (4) 32 33 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 34 35 D.42 36 How long after the occurrence of the death were the cases typically reviewed? (4b) 37 http://bmjopen.bmj.com/ 38 ○ Within one week of the death 39 40 ○ Within one month of the death 41 42 ○ Within 3 months of the death 43 44 ○ Other, please specify: ______45 on September 25, 2021 by guest. Protected copyright. 46 ○ We did not have a set timeframe for reviewing these cases 47 48 ○ Unknown 49 50 51 52 53 54 55 56 57 58 59 60

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D.43 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Who usually reviewed these cases? (4c) 5 6 a. Senior management of the hospital 7 8 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 9 10 b. Cardiology chiefs 11 12 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 13 14 c. Nursing directors 15 16 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 17 18 d. Other physiciansFor participatingpeer in reviewthe care of patients withonly AMI 19 20 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 21 22 e. Quality Improvement/Quality Management department staff 23 24 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 25 26 D.44 Did your hospital have a designated person or group to review any of the following adverse events 27 28 in patients with AMI (i.e., on an individual case level)? (6) 29 30 a. Sentinel events (unexpected occurrence involving death or serious physical or psychological injury) 31 32 that occurred during hospitalization 33 34 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 35 36

b. Unexpected transfers from a floor (non-monitored unit) to an intensive are unit http://bmjopen.bmj.com/ 37 38 39 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 40 41 c. Catastrophic complications that occurred immediately after discharge from the hospital 42 43 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 44 45 D.45 How long after the occurrence of these adverse events were the cases typically reviewed? (6a) on September 25, 2021 by guest. Protected copyright. 46 47 ○ Within one week of the adverse event 48 49 ○ Within one month of the adverse event 50 51 ○ Within 3 months of the adverse event 52 53 ○ Other, please specify: ______54 55 ○ We did not have a set timeframe for reviewing these cases 56 57 ○ Unknown 58 59 60

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D.46 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Who usually reviewed these cases? (6b) 5 6 a. Senior management of the hospital 7 8 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 9 10 b. Cardiology chiefs 11 12 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 13 14 c. Nursing directors 15 16 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 17 18 d. Other physiciansFor participating peer in the carereview of patients with AMIonly 19 20 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 21 22 e. Quality Improvement/Quality Management department staff 23 24 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 25 26 f. Other, please specify: ___ 27 28 D.47 Did your hospital use root cause analysis or a similar method to understand the following problems in 29 30 AMI care? 31 32 a. Poor adherence to the core medication (i.e., anti-platelet agents) measures 33 34 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 35 36

b. Delay to fibrinolytic therapy or percutaneous coronary intervention (PCI) http://bmjopen.bmj.com/ 37 38 39 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 40 41 D.48 Did your hospital review data on 30-day mortality rates (deaths occurring within 30 days of 42 43 admission, including both inpatient and post-discharge deaths) in patients admitted with AMI (Check 44 45 all that apply) (10) on September 25, 2021 by guest. Protected copyright. 46 47 □ Yes, through the medical insurance data system 48 49 □ Yes, through a regional database system 50 51 □ Yes, we internally collect our own data on deaths 52 53 □ Yes, other, please specify: ___ 54 55 □ No [Skip to D52] 56 57 □ Unknown 58 59 60

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D.49 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 How quickly were mortality rates in patients with AMI available to your hospital (i.e., what 5 6 was the most current data available to your hospital)? (10a) 7 8 ○ Within 6 months of care delivery 9 10 ○ 6 months to 1 year after care delivery 11 12 ○ 1 - 2 years after care delivery 13 14 ○ Less frequently than 2 years of care delivery 15 16 ○ Unknown 17 18 D.50 Did your For hospital regularlypeer compare review its performance toonly other hospitals on either inpatient in 19 20 patients with AMI? (14) 21 22 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 23 24 25 D.51 Did your hospital have efforts to improve any of the following inpatient acute myocardial infarction 26 27 (AMI) quality measures? (1) 28 29 a. Adherence to the core medication (i.e., anti-platelet agents) measures 30 31 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 32 33 b. Time to fibrinolytic therapy or percutaneous coronary intervention (PCI) 34 35 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 36 http://bmjopen.bmj.com/ 37 D.52 Beyond these quality measures, did your hospital initiate efforts to improve any of the following in 38 39 patients admitted with AMI? (2) 40 41 a. Inpatient mortality in patients with AMI 42 43 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 44 45 on September 25, 2021 by guest. Protected copyright. b. Post-discharge mortality (death occurring after discharge, but within 30 days of admission) in 46 47 patients with AMI 48 49 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 50 51 c. Readmission within 30 days from prior admission in patients with AMI 52 53 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 54 55 56 57 58 59 60

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D.53 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Did your hospital have a quality improvement team(s) devoted to improving: (3) 5 6 a. Inpatient mortality in patients with AMI 7 8 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 9 10 b. Post-discharge mortality (death occurring after discharge, but within 30 days of admission) in 11 12 patients with AMI 13 14 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 15 16 D.54 3a. Please indicate members of either the inpatient or post-discharge mortality team(s). 17 18 a. Senior managementFor of peerthe hospital review only 19 20 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 21 22 b. Hospital governing board 23 24 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 25 26 c. Chief of cardiology 27 28 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 29 30 d. Nursing directors 31 32 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 33 34 e. Other physicians participating in the care of patients with AMI 35 36

○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always http://bmjopen.bmj.com/ 37 38 39 f. Quality Improvement/Quality Management department staff 40 41 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 42 43 g. Other please specify: ______44 45 D.55 Nurses are engaged in efforts to improve AMI care. (53) on September 25, 2021 by guest. Protected copyright. 46 47 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 48 49 D.56 Cardiologists are engaged in efforts to improve AMI care. (54) 50 51 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 52 53 54 D.57 Emergency medicine physicians are engaged in efforts to improve AMI care. (55) 55 56 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 57 58 59 60

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D.58 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Did your hospital have one or more physician champions focused on improving either inpatient or 30- 5 6 day mortality in patients with AMI? (12) 7 8 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 9 10 D.59 Did your hospital have one or more nurse champions focused on improving either inpatient or 30-day 11 12 mortality in patients with AMI? (13) 13 14 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 15 16 D.60 17 After we make changes to improve AMI care, we fail to evaluate their effectiveness. (67) 18 For peer review only 19 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 20 21 D.61 Did cardiology and emergency department staff meet together to review care for patients with AMI? 22 23 (15) 24 25 ○ Yes, about monthly 26 27 ○ Yes, about quarterly 28 29 ○ Yes, about annually 30 31 ○ Yes, other: ______32 33 ○ No [Skip to D63] 34 35 ○ Unknown 36 37 http://bmjopen.bmj.com/ D.62 38 What was typically discussed at these meetings? (15a). 39 40 a. Care of patients with ST-elevation myocardial infarction (STEMI) 41 42 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 43 44 b. Care of patients with Unstable Angina/non-STEMI (NSTEMI) 45 on September 25, 2021 by guest. Protected copyright. 46 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 47 48 c. Care of patients with chest pain, in general 49 50 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 51 52 53 54 55 56 57 58 59 60

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D.63 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Did clinicians from your hospital meet with emergency medical system (EMS) providers to review the 5 6 care of patients with AMI? (16) 7 8 ○ Yes, about monthly 9 10 ○ Yes, about quarterly 11 12 ○ Yes, about annually 13 14 ○ Yes, other: ______15 16 ○ No 17 18 ○ Unknown For peer review only 19 20 D.64 There is good coordination among the different departments involved with the care of patients with 21 22 AMI. (62) 23 24 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 25 26 27 D.65 Departments caring for patients with AMI (e.g., cardiology, emergency medicine) communicate easily 28 29 with each other.(64) 30 31 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 32 33 D.66 Clinicians caring for patients with AMI share new evidence-based approaches with the AMI team.(63) 34 35 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 36 37 http://bmjopen.bmj.com/ D.67 38 Which best describes the quality of your interaction with hospitals that referred patients to you with 39 40 AMI?(18) 41 42 ○ Very collaborative (we shared data along with strategies for improving AMI care) ○ Somewhat 43 44 collaborative (we communicated regularly, but we did not share data and strategies) 45 on September 25, 2021 by guest. Protected copyright. 46 ○ Not collaborative (we had no or minimal contact with the referring hospital/s) 47 48 ○ Not applicable [Skip to D69] 49 50 51 52 53 54 55 56 57 58 59 60

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D.68 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Did your hospital routinely give feedback to the referring hospital/s on any of the following? 5 6 (18a.) 7 8 a. Time to transfer 9 10 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 11 12 b. AMI-related procedures performed 13 14 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 15 16 c. Patient outcome 17 18 ○ NeverFor ○ Rarely peer○ Sometimes ○review Usually ○ Always only 19 20 d. Other please specify: ______21 22 D.69 Which best describes the quality of your interaction with hospitals that you referred patients to with 23 24 AMI? (19) 25 26 ○ Very collaborative (we shared data along with strategies for improving AMI care) ○ Somewhat 27 28 collaborative (we communicated regularly, but we did not share data and strategies) 29 30 ○ Not collaborative (we had no or minimal contact with hospitals in our region) 31 32 ○ Not applicable 33 34 35 D.70 Was your hospital part of a regional effort or consortium of hospitals to improve AMI care? (20) 36 37 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 C. Definition of In-hospital Complications BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 1) Re-infarction 7 8 Indicate if there is physician documentation of recurrent myocardial infarction during hospitalization. 9 10 11 12 2) Cardiogenic shock 13 14 Indicate if there is physician documentation of cardiogenic shock during hospitalization. 15 16 17 18 3) Ischemic strokeFor peer review only 19 20 Indicate if there are physician documentations of new-onset ischemia stroke and stroke-related 21 22 symptoms during hospitalization. The stroke-related symptoms include: trouble walking/loss of 23 24 balance/incoordination, one-sided numbness or hemi-anesthesia, one-sided facial numbness or hemi- 25 26 anesthesia, mouth askew and drooling, dysarthria or slurred speech, loss of vision or blurred version in 27 28 one or both eyes, dizziness with vomiting, severe headache and vomiting, unconsciousness, and 29 30 hyperspasmia. 31 32 33 34 4) Congestive heart failure 35 36 Indicate if there is physician documentation of heart failure during hospital stay. This include those 37 http://bmjopen.bmj.com/ 38 without a history of heart failure but develop heart failure during hospitalization, and those with a 39 40 history of heart failure as a chronic comorbidity and develop worsening heart failure during 41 42 hospitalization. 43 44 45 on September 25, 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 D. Correlations between positive response rate of LOS-27 and IV magnesium sulfate BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 use 7 8 100% 9 10 80% 11 60% 12 13 40% 14 20% 15 16 0% 17 0% 20% 40% 60% 80% 100% 18 -20% For peer review only 19 -40%

20 from 2011 to 2015 21 -60% 22 -80% 23 use reduction IV magnesium sulfate -100% 24 Positive response rate of LOS-27 25 26 27 28 29 100% 30 90% 31 32 80% 33 70% 34 35 60% 36 50% 37 http://bmjopen.bmj.com/ 40% 38 39 30%

40 2015 sulfate use in 20% 41 42 10% 43 0%

44 rate of IV magnesium Risk-standardized 0% 20% 40% 60% 80% 100% 45 Positive response rate of LOS-27 on September 25, 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 E. Comparisons between patients with and without IV magnesium sulfate therapy after BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 propensity score matching 7 8 Characteristics Use N(%) Non-Use(%) P value 9 Patient characteristics 10 11 Age 12 13 55-64 1072(24.4) 1037(23.6) .794 14 15 65-74 1290(29.4) 1283(29.2) 16 17 <55 938(21.3) 959(21.8) 18 For peer review only 19 >=75 1094(24.9) 1115(25.4) 20 21 Gender 22 23 Female 1346(30.6) 1299(29.6) .274 24 25 Male 3048(69.4) 3095(70.4) 26 27 Hypertension 2247(51.1) 2196(50) .277 28 29 889(20.2) 878(20) .77 30 Diabetes 31 235(5.3) 244(5.6) .672 32 Dyslipidemia 33 1496(34) 1470(33.5) .558 34 Currently smoking 35 36 Number of risk factors 37 http://bmjopen.bmj.com/ 2055(46.8) 1997(45.4) .445 38 1 39 1049(23.9) 1047(23.8) 40 2 41 232(5.3) 229(5.2) 42 >=3 43 1058(24.1) 1121(25.5) 44 None 45 on September 25, 2021 by guest. Protected copyright. 546(12.4) 484(11) .04 46 Prior ischemic stroke 47 Prior myocardial infarction 416(9.5) 382(8.7) .207 48 49 Prior CABG/PCI 104(2.4) 107(2.4) .834 50 51 Chest discomfort 4021(91.5) 4046(92.1) .331 52 65(1.5) 44(1) .043 53 Left branch block at presentation 54 Cardiac arrest at presentation 81(1.8) 79(1.8) .873 55 56 Cardiogenic shock at presentation 279(6.3) 236(5.4) .051 57 58 Acute stroke at presentation 77(1.8) 66(1.5) .354 59 60

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.733 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 Heart rate at presentation, bpm 5 6 <50 177(4) 183(4.2) 7 8 50-110 3886(88.4) 3898(88.7) 9 10 >110 331(7.5) 313(7.1) 11 12 SBP at presentation, mmHg .621 13 14 <120 1565(35.6) 1607(36.6) 15 16 120-139 1299(29.6) 1307(29.7) 17 18 140-159 For peer review913(20.8) only899(20.5) 19 20 >=160 617(14) 581(13.2) 21 22 Reperfusion therapies .941 23 24 No reperfusion 3130(71.2) 3131(71.3) 25 26 Fibrinolytic therapy 746(17) 754(17.2) 27 28 Primary PCI 518(11.8) 509(11.6) 29 30 Hospital characteristics 31 32 Teaching hospital 3462(78.8) 3530(80.3) .072 33 34 Hospital level .451 35 36 Secondary or lower 1576(35.9) 1610(36.6) 37 http://bmjopen.bmj.com/ 38 Tertiary 2818(64.1) 2784(63.4) 39 40 Economic geographic region 41 42 Central 1115(25.4) 1186(27) .191 43 44 Eastern 2360(53.7) 2288(52.1) 45 on September 25, 2021 by guest. Protected copyright. 46 Western 919(20.9) 920(20.9) 47 48 Urban/Rural 49 50 Rural 1724(39.2) 1721(39.2) .948 51 52 Urban 2670(60.8) 2673(60.8) 53 54 55 56 57 58 59 60

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1 2 STROBE Statement—Checklist of items that should be included in reports of case-control studies 3 4 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 Item Page 6 No Recommendation No 7 Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the 3 8 abstract 9 (b) Provide in the abstract an informative and balanced summary of what was 10 3 11 done and what was found 12 Introduction 13 Background/rationale 2 Explain the scientific background and rationale for the investigation being 14 5 15 reported 16 Objectives 3 State specific objectives, including any prespecified hypotheses 5 17 18 Methods For peer review only 19 Study design 4 Present key elements of study design early in the paper 6 20 Setting 5 Describe the setting, locations, and relevant dates, including periods of 21 6，7 recruitment, exposure, follow-up, and data collection 22 23 Participants 6 (a) Give the eligibility criteria, and the sources and methods of case 7 24 ascertainment and control selection. Give the rationale for the choice of cases 25 and controls 26 27 (b) For matched studies, give matching criteria and the number of controls per 28 case 29 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and 7 30 effect modifiers. Give diagnostic criteria, if applicable 31 7 32 Data sources/ 8* For each variable of interest, give sources of data and details of methods of 33 measurement assessment (measurement). Describe comparability of assessment methods if 34 there is more than one group 35 Bias 9 Describe any efforts to address potential sources of bias 9 36 6 http://bmjopen.bmj.com/ 37 Study size 10 Explain how the study size was arrived at 38 Quantitative 11 Explain how quantitative variables were handled in the analyses. If applicable, 8，9 39 variables describe which groupings were chosen and why 40 8 41 Statistical methods 12 (a) Describe all statistical methods, including those used to control for 42 confounding 43 (b) Describe any methods used to examine subgroups and interactions 8 44

(c) Explain how missing data were addressed on September 25, 2021 by guest. Protected copyright. 45 9 46 (d) If applicable, explain how matching of cases and controls was addressed 47 (e) Describe any sensitivity analyses 48 49 Results 50 Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers 10 51 potentially eligible, examined for eligibility, confirmed eligible, included in the 52 study, completing follow-up, and analysed 53 23 54 (b) Give reasons for non-participation at each stage 55 (c) Consider use of a flow diagram 23 56 Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) 21， 57 22 and information on exposures and potential confounders 58 59 (b) Indicate number of participants with missing data for each variable of 60 interest Outcome data 15* Report numbers in each exposure category, or summary measures of exposure 11，25

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1 2 3 25 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 26 5 and their precision (eg, 95% confidence interval). Make clear which confounders 6 were adjusted for and why they were included 7 (b) Report category boundaries when continuous variables were categorized 21， 8 22 9 (c) If relevant, consider translating estimates of relative risk into absolute risk for 10 a meaningful time period 11 12 Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity 13 analyses 14 15 16 Discussion 17 Key results 18 Summarise key results with reference to study objectives 12,13 18 Limitations 19 DiscussFor limitations peer of the study, review taking into account only sources of potential bias or 14,15 19 20 imprecision. Discuss both direction and magnitude of any potential bias 21 Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, 12,15 22 multiplicity of analyses, results from similar studies, and other relevant evidence 23 Generalisability 21 Discuss the generalisability (external validity) of the study results 15 24 25 Other information 26 Funding 22 Give the source of funding and the role of the funders for the present study and, if 16 27 applicable, for the original study on which the present article is based 28 29 30 *Give information separately for cases and controls. 31 32 33 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 34 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 35 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 36

http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is http://bmjopen.bmj.com/ 37 38 available at http://www.strobe-statement.org. 39 40 41 42 43 44 45 on September 25, 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 Methods Paper 2 3 4 5 The China Patient-Centered Evaluative Assessment of 6 Cardiac Events (China PEACE) Retrospective Study of 7 8 Acute Myocardial Infarction: Study Design 9 10 Kumar Dharmarajan, MD, MBA*; Jing Li, MD, PhD*; Xi Li, MD, PhD; Zhenqiu Lin, PhD; 11 Harlan M. Krumholz, MD, SM†; Lixin Jiang, MD, PhD†; for the China PEACE Collaborative Group 12 13 Background—Cardiovascular diseases are rising as a cause of death and disability in China. To improve outcomes for 14 patients with these conditions, the Chinese government, academic researchers, clinicians, and >200 hospitals have created 15 China Patient-Centered Evaluative Assessment of Cardiac Events (China PEACE), a national network for research and 16 performance improvement.For The first peer study from Chinareview PEACE, the Retrospective only Study of Acute Myocardial Infarction 17 (China PEACE-Retrospective AMI Study), is designed to promote improvements in acute myocardial infarction (AMI) 18 quality of care by generating knowledge about the characteristics, treatments, and outcomes of patients hospitalized with 19 AMI across a representative sample of Chinese hospitals during the past decade. 20 Methods and Results—The China PEACE-Retrospective AMI Study will examine >18 000 patient records from 162 21 hospitals identified using a2-stage cluster sampling design within economic–geographic regions. Records were chosen 22 from 2001, 2006, and 2011 to identify temporal trends. Data quality will be monitored by a central coordinating center 23 and will, in particular, address case ascertainment, data abstraction, and data management. Analyses will examine patient 24 characteristics, diagnostic testing patterns, in-hospital treatments, in-hospital outcomes, and variation in results by time 25 and site of care. In addition to publications, data will be shared with participating hospitals and the Chinese government 26 to develop strategies to promote quality improvement. 27 Conclusions—The China PEACE-Retrospective AMI Study is the first to leverage the China PEACE platform to better 28 understand AMI across representative sites of care and during the past decade in China. The China PEACE collaboration 29 among government, academicians, clinicians, and hospitals is poised to translate research about trends and patterns of Downloaded from http://ahajournals.org by on July 28, 2019 30 AMI practices and outcomes into improved care for patients. 31 Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01624883. 32 (Circ Cardiovasc Qual Outcomes. 2013;6:732-740.) http://bmjopen.bmj.com/ 33 34 Key Words: epidemiology ◼ morbidity ◼ mortality ◼ myocardial infarction 35 36 schemic heart disease has significant public health impor- presence of significant exposure to cigarette smoke7,17,18 and 37 1,2 3,4 19 38 Itance in China. Unlike in the United States, age- air pollution. Population aging is further contributing to ris- standardized ischemic heart disease incidence is rising in ing ischemic heart disease incidence.10 39 5–10

China. Reasons for this trend include the increasing prev- To improve outcomes for ischemic heart disease and other on September 25, 2021 by guest. Protected copyright. 40 alence of traditional risk factors for atherosclerosis,6,7,10–12 cardiovascular diseases in China, the China National Center for 41 including hypertension,6,7 hyperlipidemia,7,13 diabetes mel- Cardiovascular Disease (NCCD), the Yale-New Haven Hospital 42 litus,7,13 obesity,13–16 and inadequate physical activity6,7 in the Center for Outcomes Research and Evaluation, the Chinese 43 44 Received June 26, 2013; accepted September 17, 2013. 45 From The China PEACE Collaborative Group: State Key Laboratory of Cardiovascular Disease, China Oxford Centre for International Health Research, 46 Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's 47 Republic of China; and The Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT; Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT (K.D., Z.L., H.M.K.); Division of Cardiology, Columbia University Medical Center, New York, 48 NY (K.D.); State Key Laboratory of Cardiovascular Disease, China Oxford Centre for International Health Research, Fuwai Hospital, National Center for 49 Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China (J.L., X.L., L.J.); 50 Section of Cardiovascular Medicine and the Robert Wood Johnson Clinical Scholars Program, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (H.M.K.); and Department of Health Policy and Management, Yale School of Public Health, New Haven, CT (H.M.K.). 51 *Dr Dharmarajan and Dr J. Li are joint first authors. 52 †Drs Krumholz and Jiang are joint senior authors. 53 This manuscript was handled independently by Kirsten Bibbins-Domingo, MD, PhD, MS, as a Guest Editor. The Editors had no role in the evaluation of the manuscript or in the decision about its acceptance. 54 The online-only Data Supplement is available at http://circoutcomes.ahajournals.org/lookup/suppl/doi:10.1161/CIRCOUTCOMES.113.000441/-/DC1. 55 Correspondence to Lixin Jiang, State Key Laboratory of Cardiovascular Disease, China Oxford Center for International Health Research, Fuwai Hospital, 56 National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Rd, Beijing 100037, People’s Republic of China. E-mail [email protected] 57 © 2013 American Heart Association, Inc. 58 Circ Cardiovasc Qual Outcomes is available at http://circoutcomes.ahajournals.org DOI: 10.1161/CIRCOUTCOMES.113.000441 59 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 60 732 BMJ Open Page 68 of 75 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from Dharmarajan et al China PEACE-Retrospective AMI Study Design 733 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 Figure 1. The China Patient-Centered Evaluative Assessment of Cardiac Events (PEACE) initiative. Key partners include the Chinese government, collaborating hospitals, the China National Center for Cardiovascular Disease, and the Yale-New Haven Hospital Center for 26 Outcomes Research and Evaluation. The China PEACE-Retrospective AMI Study is 1 of 5 initial studies from the China PEACE initiative. 27 The topic areas for these 5 projects concern acute myocardial infarction, coronary catheterization/percutaneous coronary intervention, 28 and multi-vessel coronary artery disease. Future studies will focus on cerebrovascular disease and other cardiovascular conditions. 29 3VD indicates revascularization in patients with triple-vessel disease; AMI, acute myocardial infarction; and PCI, percutaneous coronary

Downloaded from http://ahajournals.org by on July 28, 2019 intervention. 30

31 23–25 26,27

government, and >200 Chinese hospitals have collaborated to metropolitan areas, a small subset of provinces, or to http://bmjopen.bmj.com/ 32 create a national network for research and performance improve- patients from clinical trial databases,28 all of whom may not be 33 ment. This platform, entitled China PEACE (Patient-Centered representative of typical patients. Research involving a larger 34 Evaluative Assessment of Cardiac Events), will permit rapid and more diverse distribution of study sites has contributed 35 bidirectional flow of information between partnering hospitals to our understanding of the use of evidence-based therapies 36 and the coordinating center at the NCCD (Figure 1). With fund- after AMI,29 including differences in treatment between sec- 37 ing from the Chinese government, China PEACE will elucidate ondary and tertiary hospitals30 as well as in-hospital complica- 38 the clinical epidemiology of cardiovascular disease treatment tions such as bleeding31 and recurrent angina,32 but it has not 39 and its associated outcomes across patients, hospitals, regions, involved a large, nationally representative study population and 40 and time. China PEACE, envisioned as a combined research and has not examined temporal trends in AMI treatment and out- on September 25, 2021 by guest. Protected copyright. 41 quality improvement initiative, will disseminate findings of the comes. These trends over time, in particular, may reflect major 42 greatest relevance to participating hospitals and the Chinese gov- changes in the Chinese healthcare system that have occurred 43 ernment in a manner suitable for the evaluation of care and the in the past decade such as the expansion of health insurance 44 development of projects to improve clinical quality and patient from 30% to 90% of the population between 2001 and 2011,33 45 outcomes. Through the use of strategies most often used by clini- greatly increased resources for rural healthcare beginning in 46 cal trials, data quality will be ensured by rigorous monitoring by 2003,34 and further health reforms starting in 2009.35 Data 47 the central coordinating center at the stages of case ascertain- relating these health reforms to changing healthcare practices 48 ment, data abstraction, and data management. The collabora- are limited. To address these gaps in knowledge, the China 49 tive research and performance improvement network created by PEACE-Retrospective AMI Study will identify trends using 50 China PEACE will ultimately be leveraged to improve patient a nationally representative sample of >18 000 patient records 51 outcomes for a broad range of conditions and may be a model for from 162 randomly selected hospitals for 2001, 2006, and 52 research and quality improvement in other international settings. 2011. The hospitals represent diverse geographic regions and The first study from the China PEACE collaboration is the include institutions with a range of cardiovascular facilities. 53 Retrospective Study of Acute Myocardial Infarction (China Thus, this is the first truly national assessment of practice pat- 54 PEACE-Retrospective AMI Study). Previous research on the terns and outcomes for AMI performed in China. 55 characteristics, treatments, and outcomes for patients hospi- The China PEACE-Retrospective AMI Study broadly aims 56 talized with acute myocardial infarction (AMI) in China has to promote improvements in AMI quality of care by generating 57 contributed important knowledge but has been largely limited knowledge about the characteristics, treatments, and outcomes 58 to studies from tertiary care centers in urban regions,20–22 major of patients hospitalized with AMI across a representative 59 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 60 Page 69 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 734 Circ Cardiovasc Qual Outcomes November 2013 1 2 sample of Chinese hospitals during the past decade. The study areas, as well as among the 3 official economic–geographic regions of 3 is largely descriptive, and rather than test a specific hypothesis, Mainland China, we separately identified hospitals in 5 strata: Eastern- 4 it seeks to characterize current AMI care and associated patient rural, Central-rural, Western-rural, Eastern-urban, and Central/ 5 Western-urban regions. We considered an area urban if it is part of outcomes to provide a foundation for future quality improve- 6 a downtown or suburban area within a direct-controlled municipality ment and research. We do anticipate that there will be marked (Beijing, Tianjin, Shanghai, Chongqing) or 1 of 283 prefectural-level 7 variation in practice and outcomes, demographic and geo- cities. We considered surrounding county-level regions, including 8 graphic disparities, and ample opportunities for improvements. counties and county-level cities, to be rural. Within this framework, Mainland China is composed of 287 urban regions and 2010 rural 9 The specific aims of the China PEACE-Retrospective AMI 10 regions. We considered Central and Western-urban regions together Study are to (1) describe the characteristics of patients hospi- given their similar per capita income and health services capacity.36 11 talized with AMI in China, including their clinical and demo- We identified cases for study inclusion using a stratified 2-stage 12 graphic attributes such as occupation and insurance status; (2) cluster sampling design (Figure 2). In the first stage, we identified 13 characterize patterns of in-hospital treatment, including the use hospitals using a simple random sampling procedure within each of the 5 study strata. In the 3 rural strata, the sampling framework 14 of traditional Chinese medicines; (3) describe mortality rates consisted of the central hospital in each of the predefined rural re- 15 and other in-hospital outcomes, including the development gions (2010 central hospitals in 2010 rural regions). Within each rural 16 of heart failure and complicationsFor of treatment; peer (4) determine review region, the centralonly hospital is the largest general hospital with the 17 trends over time in patient characteristics, treatments, and out- greatest clinical capacity for treating acute illness, including AMI. In comes; (5) develop and test prognostic scores to stratify risk; each of the 2 urban strata, the sampling framework consisted of the 18 highest-level hospitals in each of the predefined urban regions (833 19 (6) compare treatment across regions and hospitals and deter- hospitals in 287 urban regions). Hospital level is officially defined 20 mine whether differences in treatment patterns by setting may by the Chinese government based on clinical resource capacity.37 For 21 be associated with differences in outcomes; (7) examine the example, secondary hospitals have ≥100 inpatient beds and the capacity to provide acute medical care and preventive care services to 22 alignment of diagnostic testing and treatment strategies with quality measures; (8) compare differences in patient character- populations of ≥100 000, whereas tertiary hospitals are large referral 23 centers in provincial capitals and major cities.29 We excluded military 24 istics, treatment approaches, and outcomes between China and hospitals, prison hospitals, specialized hospitals without a cardiovas- 25 other countries; (9) determine the quality of documentation cular disease division, and traditional Chinese medicine hospitals. We within the medical record; and (10) collaborate with participat- decided to select representative hospitals from 2011 to reflect current 26 ing hospitals and the Chinese government to disseminate study practices and trace this hospital cohort backward to 2006 and 2001 to 27 findings to improve quality of care and outcomes. describe temporal trends. As the hospital number has grown by ≈18% 28 during the past decade,36,38 the study cohort should be most represen- This article describes study methodology, abstracted data 29 tative of national treatment patterns and outcomes in 2011. Downloaded from http://ahajournals.org by on July 28, 2019 elements, analytic plan, and preliminary findings of the China In the second stage, we drew cases based on the local hospital da- 30 PEACE-Retrospective AMI Study. Findings will identify oppor- tabase for patients with AMI at each sampled hospital using system- 31 tunities for quality improvement and guide the development of atic random sampling procedures. In each of the 5 study strata, we determined the sample size required to achieve a 2% precision for http://bmjopen.bmj.com/ 32 strategies and tools to improve outcomes for AMI in China. 33 describing the primary outcome, in-hospital mortality, which we had estimated to be ≈9% in urban hospitals and 7% in rural county-level 34 Methods hospitals.5 To achieve a precision of 2% with an α of 0.05 in each 35 of the 3 rural strata, assuming an intraclass correlation of 0.02 and 36 Design Overview design effect of 1.8, we would need to sample 1150 medical records 37 The China PEACE-Retrospective AMI Study will examine >18 000 among hospitals with an average cluster size of 40. Analogously, to hospitalizations for AMI from a nationally representative network achieve a precision of 2% with an α of 0.05 in each of the 2 urban 38 of Chinese hospitals during 2001, 2006, and 2011. The study in- strata, assuming an intraclass correlation of 0.02 and design effect of 39 cludes hospitalizations with a principal discharge diagnosis of AMI 2.2, we would need to sample 1750 medical records among hospitals 40 (International Classification of Diseases, Ninth Revision, Clinical with an average cluster size of 60. These cluster sizes in rural and ur- on September 25, 2021 by guest. Protected copyright. Modification codes 410.xx or International Classification of Diseases, ban settings seemed reasonable based on our previous survey of treat- 41 Tenth Revision, Clinical Modification codes I21.xx), including ST- ment for acute coronary syndromes at >1000 hospitals in 2010, which 42 segment–elevation myocardial infarction and non–ST-segment– demonstrated that the median volume of hospitalization for AMI was 43 elevation myocardial infarction. We did not include hospitalizations ≈180 annual cases in urban hospitals and 95 annual cases in rural 44 with a principal discharge diagnosis of unstable angina. county-level hospitals. Assuming a participation rate of 85% among To study 10-year trends in patient characteristics, treatment patterns, selected hospitals, we approached 35 hospitals for participation in 45 and outcomes nationally and within regions of different socioeconomic each stratum for a total of 175 hospitals (70 urban and 105 rural). We 46 development, we drew a random, representative sample of patient dis- doubled cluster sizes for 2011 to improve precision in the description 47 charges for each year. We intentionally drew a larger sample for 2011 to of hospital-level treatment patterns and outcomes. Consequently, the 48 study differences in treatment patterns and outcomes across hospitals. total expected sample volume with the above assumptions was ≈6950 The central ethics committee at the China NCCD approved the cases in 2001, 6950 cases in 2006, and 13 900 cases in 2011. A more 49 PEACE-Retrospective AMI Study. All collaborating hospitals accept- detailed description of the sampling strategy used in the PEACE- 50 ed the central ethics approval except for 5 hospitals, which obtained Retrospective AMI Study is provided in the supplemental material. 51 local approval by internal ethics committees. The study is listed at 52 www.clinicaltrials.gov (NCT01624883). Data Collection The Chinese government, which provided financial support for the 53 We trained staff at participating hospitals to identify all hospitaliza- study, had no role in the design or conduct of the study; in the collec- tions for AMI from their respective local hospital databases for the 54 tion, management, analysis, and interpretation of the data; or in the years 2001, 2006, and 2011. After we sampled cases at each hospi- 55 preparation or approval of the article. tal, we assigned each case a unique study ID. We then required local 56 investigators to gather the original record, scan it, and transmit the 57 Sampling Design scanned copy to the coordinating center. To facilitate this process, We intended study hospitals to reflect diverse sites of care in China. As the coordinating center provided each study site with a high-speed 58 hospital volumes and clinical capacities differ between urban and rural scanner. To verify compliance with the case finding strategy, research 59 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 60 BMJ Open Page 70 of 75 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from Dharmarajan et al China PEACE-Retrospective AMI Study Design 735 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 Downloaded from http://ahajournals.org by on July 28, 2019 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 Figure 2. China Patient-Centered Evaluative Assessment of Cardiac Events (PEACE) Retrospective Study of Acute Myocardial Infarction 49 flow chart and associated quality assurance strategies. Flow chart should be read from top to bottom. CRF indicates case report form; 50 NCCD, China National Center for Cardiovascular Diseases; and Q&A, questions and answers. 51 52 staff from the study coordinating center visited 46 study sites to re- poorly scanned records were rescanned and retransmitted (Figure 2). 53 peat the case finding process, confirm that the list of hospitalizations We instructed study sites to include all parts of the medical record, with AMI was complete, and assist in acquiring the sampled cases including the face sheet, admission note, daily progress notes, proce- 54 (Figure 2). These 46 sites provided ≈50% of sampled cases for the dure notes, medication administration record, diagnostic procedure 55 China PEACE-Retrospective AMI Study. reports, laboratory test results, physician orders, nursing notes, and 56 After identifying all medical records for sampled cases, partici- discharge summary. These subdivisions of the medical record are 57 pating hospitals copied and transmitted the records to the NCCD routinely present throughout China. after deidentification. Research staff ensured the completeness and The China PEACE-Retrospective AMI Study has adhered to rig- 58 quality with which each medical record was scanned; incomplete or orous standards for abstraction. Before initiating chart review, each 59 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 60 Page 71 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 736 Circ Cardiovasc Qual Outcomes November 2013 1 2 abstractor received 2 weeks of training that included an introduc- 3 Data Elements tion to the study and instruction about coronary heart disease and its We examined both the English language and the Chinese literature for 4 subtypes, component parts of the inpatient medical record including relevant studies to create a candidate list of potential data elements. 5 specialized sections such as catheterization reports, and the China Where possible, we included elements particular to the Chinese con- 6 PEACE-Retrospective AMI Study data dictionary. We provided all text such as the use of traditional Chinese medicines. We supplement- material, including the data dictionary, in Chinese. After training, we 7 ed these elements with variables used in the Get with the Guidelines certified trainees who were able to abstract 10 sample medical re- ACTION (Acute Coronary Treatment and Intervention Outcomes 8 cords with >98% accuracy (online-only Data Supplement). Network) Registry of the National Cardiovascular Data Registry 9 The China PEACE-Retrospective AMI Study used several strate- (NCDR) and the Variation in Recovery: Role of Gender on Outcomes 10 gies to improve the accuracy of abstraction. Inexperienced abstrac- of Young Acute Myocardial Infarction Patients (VIRGO) study. tors began with exclusively typewritten rather than hand written 11 ACTION is an outcome-based registry and quality improvement pro- medical records. In addition, we randomly audited ≈5% of the ab- gram that focuses on patients hospitalized with ST-segment–elevation 12 stracted records. If the records were not abstracted with 98% ac- myocardial infarction and non–ST-segment–elevation myocardial 13 curacy, all medical records in the audited batch were considered infarction.39 VIRGO is a large, observational study of the presenta- 14 unqualified and were rereviewed by a different abstractor. We used tion, treatment, and outcomes of young women and men with AMI.40 15 abstractors with formal medical training to identify data elements The use of standardized elements from ACTION and VIRGO permit requiring more advanced medical knowledge for recognition, such cross-country comparisons (Table 1). We performed pilot testing of 16 as the presence of comorbidities,For evidence ofpeer pulmonary edema review on the case report only form on >500 medical records from study sites across 17 hospital presentation, and the development of postprocedural com- China to enhance clarity of wording and further guide variable selec- 18 plications, such as bleeding or arrhythmia. A physician was always tion. We present data relevant to performance measures during the 19 present in the room with abstractors or was available online to an- first 24 hours of hospitalization and at hospital discharge in Table 2. swer questions as they arose. As problems were identified, we up- Where possible, we collected data that would allow us to construct the 20 dated the data dictionary and web-based data management program core quality measures used and reported by the Centers for Medicare 21 built for the China PEACE-Retrospective AMI Study into which data & Medicaid Services in the United States. Each participating hospital 22 were directly entered. We have additionally customized this program has also completed a survey, modeled on the annual survey of hos- to expedite the identification of medications that may have multiple pitals performed by the American Hospital Association, of its major 23 41 trade names. Finally, we assigned medical records belonging to the structural and organizational characteristics. Key variables assessed 24 same hospital and year to a broad group of reviewers to avoid po- include bed size, annual volume of AMI, teaching status, and capac- 25 tential residual disparities in quality among abstractors (online-only ity to perform invasive revascularization procedures. The patient case 26 Data Supplement). report form and associated data dictionary are available in the online- only Data Supplement. 27 28 Data Management 29 We have treated all data as protected health information and have Statistical Analyses Downloaded from http://ahajournals.org by on July 28, 2019 30 securely stored it in an encrypted and password-protected database We will report summary statistics for patient characteristics, use of 31 at the coordinating center. We have securely stored paper charts in diagnostic tests, treatments received, and in-hospital outcomes in- locked rooms. cluding complications of care across study sites. Weighting will re- http://bmjopen.bmj.com/ 32 We perform ongoing data cleaning systematically. Data managers flect the reciprocal of sampling probability. For each aim, we will use 33 regularly query data for invalid and illogical values, as well as for du- standard parametric and nonparametric techniques for observational 34 plicate record entries. They identify potential invalid values by search- data, including t tests, χ2 tests, Wilcoxon rank-sum tests, and general- 35 ing for outliers in continuous data distributions. Records with identical ized linear models. Because patient characteristics, treatments, and study identification numbers, hospital identification numbers, medical outcomes may be correlated within study sites, analyses will account 36 record identification numbers, and dates of discharge trigger a search for the effect of clustering. To examine and adjust for differences 37 for duplicate records. Once a potential error is found, data managers between comparison groups, we will use linear, logistic, Cox pro- 38 trace and review the relevant records to resolve the issue. portional hazard, and Poisson models with a generalized estimating 39 on September 25, 2021 by guest. Protected copyright. 40 Table 1. China PEACE-Retrospective Study of Acute Myocardial Infarction Data 41 Elements 42 Category Example Elements 43 44 Patient demographics Age, sex, ethnicity, postal code, occupation, and insurance status 45 Medical history Diabetes mellitus, hypertension, hyperlipidemia, vascular disease, 46 and prior revascularization 47 Initial cardiac status Heart rate, blood pressure, Killip class, heart failure, and cardiac arrest 48 Laboratory values Troponin, CK, CK-MB, BNP, sodium, BUN, creatinine, WBC count, and hemoglobin 49 Medications including Antithrombotic therapy, β-blocker, ACE inhibitor/ARB, statin, 50 dose and traditional Chinese medicines 51 Revascularization Fibrinolysis, PCI (access, anatomy, stent number, stent type, contrast dose, 52 closure device), and CABG surgery 53 Diagnostic procedures Echocardiogram, CT angiogram, stress testing, and chest radiograph 54 Outcomes including in- Death, heart failure, shock, arrhythmia, stroke, bleeding, transfusion, 55 hospital complications and infection 56 ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BNP, brain natriuretic 57 peptide; BUN, blood urea nitrogen; CABG, coronary artery bypass graft; CK, creatine kinase; CK-MB, creatine kinase-MB fraction; CT, computed tomography; PCI, percutaneous coronary intervention; PEACE, Patient- 58 Centered Evaluative Assessment of Cardiac Events; and WBC, white blood cell. 59 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 60 BMJ Open Page 72 of 75 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from Dharmarajan et al China PEACE-Retrospective AMI Study Design 737 1 2 Table 2. China PEACE-Retrospective Study of Acute However, these records were considered adequate for inclusion in the 3 Myocardial Infarction Performance Measures study. The use of electronic medical records increased with time: 0% 4 of hospitals used electronic medical records in 2001, 7% of hospitals 5 First 24 h Discharge used electronic medical records in 2006, and 46% of hospitals used electronic medical records in 2011. We will code hospital-level vari- 6 Aspirin Aspirin ables for the presence of daily progress notes and electronic medical 7 Heparin Clopidogrel records to better understand whether these factors introduce bias into 8 Evaluation of left ventricular function β-blocker study results. To verify the accuracy of principal discharge diagnoses, we ran- 9 Time to primary PCI ACE inhibitor or ARB for LV 10 domly selected 300 medical records and examined concordance systolic dysfunction between principal discharge diagnosis and electrocardiographic 11 Time to fibrinolysis Statin findings consistent with the subtype of AMI (ST-segment–elevation 12 Overall reperfusion therapy Smoking cessation counseling myocardial infarction versus non–ST-segment–elevation myocardial infarction). We found concordance in 95% of cases. 13 Cardiac rehabilitation referral 14 ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor 15 blocker; PEACE, Patient-Centered Evaluative Assessment of Cardiac Events; LV, Discussion 16 left ventricle; and PCI, percutaneous coronaryFor intervention. peer reviewAkin to the Cooperativeonly Cardiovascular Project in the United 17 States,42 China PEACE provides a platform through which 18 equation approach and hierarchical models, where appropriate. We government, healthcare providers, and research organiza- 19 will develop models to stratify patients according to their risk of ad- tions can translate knowledge of the clinical epidemiology of 20 verse outcomes. We will assess the relationship of candidate variables cardiovascular disease into improved care for patients. In the 21 to in-hospital outcomes using appropriate statistical techniques for the dependent variable. We will further refine the list of candidate United States, collaboration between the Healthcare Financ- 22 variables based on their clinical relevance. ing Administration, hospitals, and academic researchers dem- 23 onstrated frequent underuse of evidence-based therapies for 43 24 Progress to Date AMI. Rapid feedback of these findings to hospitals resulted 25 As of May 2013, 162 hospitals have agreed to participate in the China in significant improvement in performance on all studied 26 PEACE-Retrospective AMI Study (Figure 3). Of the 13 that did not quality indicators and reduced mortality.44 China PEACE 27 participate, 7 did not have admissions for AMI, and 6 declined par- has similar potential to serve as a foundational project that 28 ticipation. Examination of patient databases from participating hos- evaluates and, if necessary, elevates cardiovascular care more pitals yielded 31 601 hospitalizations for AMI (3859 in 2001, 8863 in generally within China. As with the United States in the early 29 2006, and 18 879 in 2011). Of these, we sampled 18 631 for the China Downloaded from http://ahajournals.org by on July 28, 2019 30 PEACE-Retrospective AMI Study (2801 in 2001, 5199 in 2006, and 1990s, China is turning increased attention to the treatment 45 31 10 631 in 2011). Of these 18 631 sampled hospitalizations, we ac- of patients hospitalized with acute cardiovascular conditions 32 quired medical records for 18 110 (97.2%) and began data abstraction to improve outcomes across diverse patient populations and http://bmjopen.bmj.com/ in August 2012. Medical records from 95% (154) of study sites con- sites of care. China PEACE will leverage the unique resources 33 tained all expected sections and represent 89% of all hospitalizations of the Chinese government, a diverse hospital network, and 34 in the China PEACE-Retrospective AMI Study. In the remaining 8 an international research team to translate study findings into 35 study sites, we did not have access to daily progress notes because of local administrative policies of hospital archives departments. action for the benefit of patients. 36 37 38 39 40 on September 25, 2021 by guest. Protected copyright. 41 42 43 44 45 Figure 3. Geographic distribution of 46 participating hospitals in the China Patient- 47 Centered Evaluative Assessment of Cardiac Events (PEACE) Retrospective Study of Acute 48 Myocardial Infarction (AMI). Of 175 sampled 49 hospitals, 13 were unable or unwilling to 50 participate, and 162 provided cases for the 51 China PEACE-Retrospective AMI Study. 52 53 54 55 56 57 58 59 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 60 Page 73 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 738 Circ Cardiovasc Qual Outcomes November 2013 1 2 The partnership among government, hospitals, and research- Lack of completeness may signal problems with documentation 3 ers is a critical source of strength for China PEACE. For exam- that are important to note, as detailed and reliable record keep- 4 ple, clinical champions have informed the content of case report ing is needed to measure key processes and outcomes in qual- 5 forms, thereby increasing the likelihood that study questions ity improvement. Therefore, the assessment of the quality of the 6 and findings are relevant at the front lines of care. Continuing medical record can be an important contribution of this effort. 7 conversations with hospitals will help align planned analyses The China PEACE-Retrospective AMI Study is also restricted 8 to the areas of greatest concern and uncertainty for provid- to measuring in-hospital outcomes, as we are unable to link 9 ers. The NCCD will tailor performance feedback reports to patient-level data to a national registry of deaths. However, the 10 the information needs and clinical goals of each hospital. For length of stay in Chinese hospitals, extended compared with that 11 example, the NCCD will be able to benchmark site-specific of many Western countries,5,36,46,47 should permit more robust 12 data on patient characteristics, receipt of evidence-based treat- estimates of short-term complications including death. Next, 13 ment, and outcomes to nearby hospitals, hospitals with simi- we are unable to report on hospital costs and cost-effectiveness 14 lar case mix, top performing hospitals, the full spectrum of related to care for AMI, as well as patient out-of-pocket costs, as 15 Chinese hospitals, or international institutions. In addition, the this information is not available in the standard medical record, 16 research teams will serve asFor hubs to ensure peer the rapid transreview- which only containsonly information on the total charge for hospital- 17 fer of data, including information on best practices, between ization. Finally, study precision will be slightly lower than antic- 18 hospitals, and the Chinese government. The direct ties to gov- ipated, as we collected data from ≈18 000 medical records rather 19 ernment will increase the likelihood that study findings influ- than the anticipated 28 000. This discrepancy resulted from the 20 ence policy pertinent to AMI and cardiovascular care. Such an substantially lower volume of hospitalizations for AMI than had 21 arrangement may also facilitate the creation of clinical tools to been anticipated for the years 2001 and 2006, in particular. Our 22 improve care, such as standing order templates, risk stratifica- estimates, which were based on 2010 survey data, did not fully 23 tion algorithms, and dosing pocket cards. account for the marked increase in AMI hospitalizations that we 24 China PEACE is further distinguished by its use of data identified between 2001 and 2011. However, the smaller sample 25 quality control strategies, which are much more common in size than expected should not substantively affect the precision with which major outcomes such as mortality are described, as 26 multinational clinical trials than in large retrospective studies. In particular, the China PEACE-Retrospective AMI expected strata-level precision for mortality decreased by no 27 Study has devoted significant attention to data quality at more than 2% in rural areas and no more than 1% in urban areas 28 the stages of case ascertainment, data abstraction, and data (online-only Data Supplement). 29 Downloaded from http://ahajournals.org by on July 28, 2019 management. For example, research staff rigorously moni- China PEACE will ensure transparency in research design, 30 tored study sites to identify all hospitalizations for AMI from performance, and reporting. Although the Chinese govern- 31 census databases. Staff also ensured that medical records for ment has funded China PEACE, it has no role in conduct of http://bmjopen.bmj.com/ 32 sampled cases were physically found, properly copied, and the study. We will perform all analyses in academic research 33 transmitted in full whenever possible. In addition, the China units at the China NCCD and the Yale-New Haven Hospital 34 PEACE-Retrospective AMI Study provided central train- Center for Outcomes Research and Evaluation. Government 35 ing for abstractors and required rigorous standards for both approval of articles will not be required before publication. 36 initial certification and recertification. Medical records from China PEACE is intended to spur similar collaborations 37 abstractors who did not achieve recertification requirements among government, healthcare institutions, and academic 38 were reabstracted by a second reviewer. In developing these researchers to better understand cardiovascular disease inci- 39 systems, China PEACE is also positioned for future studies. dence, treatment, and outcomes. Partnerships among local 40 The China PEACE-Retrospective AMI Study has several hospitals at the front line of care, domestic research orga- on September 25, 2021 by guest. Protected copyright. 41 additional strengths. It contains the largest representative sam- nizations with local expertise and previous track records of 42 ple of hospitalizations for AMI in China and therefore includes success, international experts in research design, and policy- 43 patients from diverse geographic regions and institutions with makers intent on improving population health can identify 44 widely varying resource capacities. Its inclusion of data from important targets for study, build novel research networks, and 45 2001, 2006, and 2011 will permit the assessment of trends in generate tools useful in improving health outcomes. These 46 patient characteristics, care patterns, and outcomes. Information partnerships can support a research and health improvement 47 will be available on topics that have not been well studied (eg, infrastructure that is unconstrained by particular diseases or 48 the use of traditional Chinese medicines after AMI). Cross- conditions and is capable of facilitating clinical trials and performance improvement activities. In the future we will seek 49 country comparisons will be possible given the alignment to involve patients and caregivers in the research team. The 50 of key data elements with the NCDR ACTION Registry and China PEACE-Retrospective AMI Study is the first of many 51 VIRGO. Finally, further targeted examination of additional data elements not included in the initial case report forms can be projects that can leverage the China PEACE platform to eluci- 52 performed as novel questions arise, as the NCCD will maintain date the patterns of care and outcomes of cardiovascular dis- 53 a physical copy of all charts after the initial abstraction. ease across patients, hospitals, and regions within China. 54 The China PEACE-Retrospective AMI Study has some limi- 55 tations. Study findings depend on the accuracy and complete- Acknowledgments 56 ness of the abstracted medical records. However, this limitation 57 We appreciate the guidance provided by Prof Liming Li (Chinese pertains to all retrospective chart reviews, including those per- Academy of Medical Sciences), Prof Zhengming Chen (University 58 formed by the Cooperative Cardiovascular Project and registries. of Oxford), Dr Jun Lv, and Dr Qiushan Tao (Peking University) with 59 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 60 BMJ Open Page 74 of 75 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from Dharmarajan et al China PEACE-Retrospective AMI Study Design 739 1 2 regard to study design. We appreciate the multiple contributions made 13. Critchley J, Liu J, Zhao D, Wei W, Capewell S. Explaining the increase 3 by study teams at the China Oxford Centre for International Health in coronary heart disease mortality in Beijing between 1984 and 1999. 4 Research and the Yale-New Haven Hospital Center for Outcomes Circulation. 2004;110:1236–1244. 5 Research and Evaluation in the realms of study design and operations. 14. Ma GS, Li YP, Wu YF, Zhai FY, Cui ZH, Hu XQ, Luan DC, Hu YH, Yang We are grateful for the support provided by the Chinese government. XG. The prevalence of body overweight and obesity and its changes 6 among Chinese people during 1992 to 2002. Zhonghua Yu Fang Yi Xue Za 7 Zhi. 2005;39:311–315. 8 Sources of Funding 15. Wu Y. Overweight and obesity in China. BMJ. 2006;333:362–363. 16. Wang H, Du S, Zhai F, Popkin BM. Trends in the distribution of body This project was partly supported by grant 201202025 from the 9 mass index among Chinese adults, aged 20-45 years (1989-2000). Int J Ministry of Health of China. Dr Dharmarajan is supported by grant 10 Obes (Lond). 2007;31:272–278. HL007854 from the National Heart, Lung, and Blood Institute; he 11 17. Yang G, Fan L, Tan J, Qi G, Zhang Y, Samet JM, Taylor CE, Becker K, is also supported as a Centers of Excellence Scholar in Geriatric Xu J. Smoking in China: findings of the 1996 National Prevalence Survey. 12 Medicine at Yale by the John A. Hartford Foundation and the JAMA. 1999;282:1247–1253. 13 American Federation for Aging Research. Dr Krumholz is supported 18. Gu D, Wu X, Reynolds K, Duan X, Xin X, Reynolds RF, Whelton PK, 14 by grant U01 HL105270-03 (Center for Cardiovascular Outcomes He J; InterASIA Collaborative Group. Cigarette smoking and expo- Research at Yale University) from the National Heart, Lung, and sure to environmental tobacco smoke in China: the international col- 15 Blood Institute. The sponsors had no role in the conduct of the study; laborative study of cardiovascular disease in Asia. Am J Public Health. 16 in the collection, management,For analysis, and peer interpretation ofreview the 2004;94:1972–1976. only 17 data; or in the preparation or approval of the article. 19. Chen R, Zhang Y, Yang C, Zhao Z, Xu X, Kan H. Acute Effect of Ambient Air Pollution on Stroke Mortality in the China Air Pollution and Health 18 Disclosures Effects Study. Stroke. 2013. 19 20. Yang XD, Zhao YS, Li YF, Guo XH. Medical comorbidities at admission is None. 20 predictive for 30-day in-hospital mortality in patients with acute myocardial infarction: analysis of 5161 cases. J Geriatr Cardiol. 2011;8:31–34. 21 References 21. Zhang H, Sun S, Tong L, Li R, Cao XH, Zhang BH, Zhang LH, Huang 22 1. He J, Gu D, Wu X, Reynolds K, Duan X, Yao C, Wang J, Chen CS, Chen JX, Ma CS. Effect of cigarette smoking on clinical outcomes of hospital- 23 J, Wildman RP, Klag MJ, Whelton PK. Major causes of death among men ized Chinese male smokers with acute myocardial infarction. Chin Med J 24 and women in China. N Engl J Med. 2005;353:1124–1134. (Engl). 2010;123:2807–2811. 2. Yang G, Wang Y, Zeng Y, Gao GF, Liang X, Zhou M, Wan X, Yu S, Jiang 22. Chu PH, Chiang CW, Cheng NJ, Ko YL, Chang CJ, Chen WJ, Kuo CT, 25 Y, Naghavi M, Vos T, Wang H, Lopez AD, Murray CJ. Rapid health tran- Hsu TS, Lee YS. Gender differences in baseline variables, therapies and 26 sition in China, 1990-2010: findings from the Global Burden of Disease outcomes in Chinese patients with acute myocardial infarction. Int J 27 Study 2010. Lancet. 2013;381:1987–2015. Cardiol. 1998;65:75–80. 3. Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS. Population 23. Wang SR, Liu HX, Zhao D, Lei Y, Wang W, Shang JJ, Fang YT, Shi ZX, 28 trends in the incidence and outcomes of acute myocardial infarction. N Huang Y, Li QL; Beijing Collaborative Study Group on Therapies Status 29 Engl J Med. 2010;362:2155–2165. of Acute Myocardial Infarction. Study on the therapeutic status of 1242 30 Downloaded from http://ahajournals.org by on July 28, 2019 4. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, hospitalized acute myocardial infarction patients in Beijing. Zhonghua Liu Bravata DM, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Xing Bing Xue Za Zhi. 2006;27:991–995. 31 Hailpern SM, Heit JA, Howard VJ, Huffman MD, Kissela BM, Kittner SJ, 24. Zhang SY, Hu DY, Sun YH, Yang JG. Current management of patients 32 Lackland DT, Lichtman JH, Lisabeth LD, Magid D, Marcus GM, Marelli with ST elevation myocardial infarction in Metropolitan Beijing, China. http://bmjopen.bmj.com/ 33 A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Clin Invest Med. 2008;31:E189–E197. Nichol G, Paynter NP, Schreiner PJ, Sorlie PD, Stein J, Turan TN, Virani 25. Song L, Hu DY, Yang JG, Sun YH, Liu SS, Li C, Feng Q, Wu D. Factors 34 SS, Wong ND, Woo D, Turner MB; American Heart Association Statistics leading to delay in decision to seek treatment in patients with acute myo- 35 Committee and Stroke Statistics Subcommittee. Heart disease and stroke cardial infarction in Beijing. Zhonghua Nei Ke Za Zhi. 2008;47:284–287. 36 statistics–2013 update: a report from the American Heart Association. 26. Yu LT, Zhu J, Mister R, Zhang Y, Li JD, Wang DL, Liu LS, Flather M. Circulation. 2013;127:e6–e245. The Chinese registry on reperfusion strategies and outcomes in ST- 37 5. Tunstall-Pedoe H, Kuulasmaa K, Mähönen M, Tolonen H, Ruokokoski elevation myocardial infarction. Zhonghua Xin Xue Guan Bing Za Zhi. 38 E, Amouyel P. Contribution of trends in survival and coronary-event rates 2006;34:593–597. 39 to changes in coronary heart disease mortality: 10-year results from 37 27. Zhang B, Jiang DM, Zhou XC, Liu J, Zhang W, Sun YJ, Ren LN, Zhang ZH, Gao Y, Li YZ, Shi JP, Qi GX. Prospective multi-center study of female WHO MONICA project populations: monitoring trends and determinants on September 25, 2021 by guest. Protected copyright. 40 in cardiovascular disease. Lancet. 1999;353:1547–1557. patients with ST-elevation myocardial infarction in Liaoning province, 41 6. Yang G, Kong L, Zhao W, Wan X, Zhai Y, Chen LC, Koplan JP. China. Chin Med J (Engl). 2012;125:1915–1919. 42 Emergence of chronic non-communicable diseases in China. Lancet. 28. Shao XH, Yang YM, Zhu J, Liu LS; China CREATE Investigation Group. 2008;372:1697–1705. Comparison on therapeutic approach and short-term outcomes between 43 7. Hu SS, Kong LZ, Gao RL, Zhu ML, Wang W, Wang YJ, Wu ZS, Chen male and female patients with ST-segment elevation myocardial infarc- 44 WW, Liu MB; Editorial Board. Outline of the report on cardiovascular tion. Zhonghua Xin Xue Guan Bing Za Zhi. 2012;40:108–114. 45 disease in China, 2010. Biomed Environ Sci. 2012;25:251–256. 29. Gao R, Patel A, Gao W, Hu D, Huang D, Kong L, Qi W, Wu Y, Yang 8. Wu Z, Yao C, Zhao D, Wu G, Wang W, Liu J, Zeng Z, Wu Y. Sino- Y, Harris P, Algert C, Groenestein P, Turnbull F; CPACS Investigators. 46 MONICA project: a collaborative study on trends and determinants in car- Prospective observational study of acute coronary syndromes in China: 47 diovascular diseases in China, Part i: morbidity and mortality monitoring. practice patterns and outcomes. Heart. 2008;94:554–560. 48 Circulation. 2001;103:462–468. 30. Liu Q, Zhao D, Liu J, Wang W, Liu J; Bridging the Gap on Coronary 9. Zhao D, Liu J, Wang W, Zeng Z, Cheng J, Liu J, Sun J, Wu Z. Heart Disease Secondary Prevention in China. Current clinical practice 49 Epidemiological transition of stroke in China: twenty-one-year ob- patterns and outcome for acute coronary syndromes in China: results of 50 servational study from the Sino-MONICA-Beijing Project. Stroke. BRIG project. Zhonghua Xin Xue Guan Bing Za Zhi. 2009;37:213–217. 51 2008;39:1668–1674. 31. Liu X, Chen YD, Lü SZ, Jin ZN, Liu H, Song XT; China GRACE 10. Moran A, Gu D, Zhao D, Coxson P, Wang YC, Chen CS, Liu J, Cheng J, Investigation Group. Analysis of the risk factors of patients with acute 52 Bibbins-Domingo K, Shen YM, He J, Goldman L. Future cardiovascular coronary syndrome sufferin hemorrhage during hospitalization. Zhonghua 53 disease in China: Markov model and risk factor scenario projections from Xin Xue Guan Bing Za Zhi. 2012;40:902–907. 54 the coronary heart disease policy model-China. Circ Cardiovasc Qual 32. Zhao FH, Chen YD, Song XT, Pan WQ, Jin ZN, Yuan F, Li YB, Ren F, Outcomes. 2010;3:243–252. Lü SZ; Sino-GRACE investigators. Predictive factors of recurrent angina 55 11. Zhang XH, Lu ZL, Liu L. Coronary heart disease in China. Heart. after acute coronary syndrome: the global registry acute coronary events 56 2008;94:1126–1131. from China (Sino-GRACE). Chin Med J (Engl). 2008;121:12–16. 57 12. Yong H, Foody J, Linong J, Dong Z, Wang Y, Ma L, Meng HJ, Shiff S, 33. Cao Q, Shi L, Wang H, Dong K. Report from China: health insurance Dayi H. A systematic literature review of risk factors for stroke in China. in China–evolution, current status, and challenges. Int J Health Serv. 58 Cardiol Rev. 2013;21:77–93. 2012;42:177–195. 59 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 60 Page 75 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 740 Circ Cardiovasc Qual Outcomes November 2013 1 2 34. Hu S, Tang S, Liu Y, Zhao Y, Escobar ML, de Ferranti D. Reform of how 42. Vogel RA. HCFA’s Cooperative Cardiovascular Project: a nation- 3 health care is paid for in China: challenges and opportunities. Lancet. wide quality assessment of acute myocardial infarction. Clin Cardiol. 4 2008;372:1846–1853. 1994;17:354–356. 5 35. Chen Z. Launch of the health-care reform plan in China. Lancet. 43. Ellerbeck EF, Jencks SF, Radford MJ, Kresowik TF, Craig AS, Gold JA, 2009;373:1322–1324. Krumholz HM, Vogel RA. Quality of care for Medicare patients with 6 36. Ministry of Health of the People’s Republic of China. China Public acute myocardial infarction: a four-state pilot study from the Cooperative 7 Health Statistical Yearbook 2011. Beijing: Peking Union Medical College Cardiovascular Project. JAMA. 1995;273:1509–1514. 8 Publishing House; 2011. 44. Marciniak TA, Ellerbeck EF, Radford MJ, Kresowik TF, Gold JA, 37. Ministry of Health of the People’s Republic of China. The Performance 9 Krumholz HM, Kiefe CI, Allman RM, Vogel RA, Jencks SF. Improving Evaluation Standards for General Hospitals (Revised Version). 2009. the quality of care for Medicare patients with acute myocardial infarc- 10 http://www.moh.gov.cn/cmsresources/mohbgt/cmsrsdocument/doc6535. tion: results from the Cooperative Cardiovascular Project. JAMA. pdf. Accessed May 28, 2013. 11 1998;279:1351–1357. 38. Ministry of Health of the People’s Republic of China. China Public 45. Chinese Center for Disease Control and Prevention. Early diagnosis and 12 Health Statistical Yearbook 2003. Beijing: Peking Union Medical College treatment are low for patients with acute myocardial infarction in China. Publishing House; 2003. 13 http://www.chinacdc.cn/mtdx/mxfcrxjbxx/201210/t20121015_70567. 14 39. Peterson ED, Roe MT, Rumsfeld JS, Shaw RE, Brindis RG, Fonarow GC, Cannon CP. A call to ACTION (acute coronary treatment and intervention htm. Accessed February 11, 2013. 15 outcomes network): a national effort to promote timely clinical feedback 46. Chen ZM, Pan HC, Chen YP, Peto R, Collins R, Jiang LX, Xie JX, Liu LS; 16 and support continuous quality improvementFor forpeer acute myocardial infarcreview- COMMIT only(Clopidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Early intravenous then oral metoprolol in 45,852 pa- 17 tion. Circ Cardiovasc Qual Outcomes. 2009;2:491–499. 40. Lichtman JH, Lorenze NP, D’Onofrio G, Spertus JA, Lindau ST, Morgan tients with acute myocardial infarction: randomised placebo-controlled 18 TM, Herrin J, Bueno H, Mattera JA, Ridker PM, Krumholz HM. Variation trial. Lancet. 2005;366:1622–1632. 19 in recovery: role of gender on outcomes of young AMI patients (VIRGO) 47. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS; 20 study design. Circ Cardiovasc Qual Outcomes. 2010;3:684–693. COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) 41. American Hospital Association. AHA Annual Survey Database Fiscal collaborative group. Addition of clopidogrel to aspirin in 45,852 patients 21 Year 2011. http://www.ahadataviewer.com/book-cd-products/aha-survey/. with acute myocardial infarction: randomised placebo-controlled trial. 22 Accessed May 27, 2013. Lancet. 2005;366:1607–1621. 23 24 25 26 27 28 29 30 Downloaded from http://ahajournals.org by on July 28, 2019 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 58 59 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 60 BMJ Open Page 76 of 75 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from

1 2 3 National Clinical Research Center for Cardiovascular Diseases 4 5 Fuwai Hospital 6 7 167 Beilishi Road 8 Beijing 100037 9 10 People’s Republic of China 11 12 13 14 July 01, 2019 15 16 For peer review only 17 18 19 Dr. Adrian Aldcroft, 20 21 Editor, 22 BMJ Open 23 24 25 26 Dear Dr. Aldcroft, 27 28 29 We are writing to submit our manuscript entitled “Use of Intravenous Magnesium Sulfate among 30 31 Patients with Acute Myocardial Infarction in China from 2001 to 2015: China PEACE- 32 http://bmjopen.bmj.com/ 33 Retrospective AMI Study” for your consideration for publication in BMJ Open. We believe this 34 manuscript is a valuable contribution to the literature examining de-adoption of ineffective 35 36 therapy in clinical practice in China and other countries. 37 38 This manuscript submitted provided a detailed analysis of the trends and variation in use of IV 39 40 magnesium sulfate in a nationally representative sample of about 24,000 patients with AMI over on September 25, 2021 by guest. Protected copyright. 41 the past fifteen tears. To our knowledge, limited data in China and other countries substantiate 42 43 this subject. In our study, we found that the de-adoption of magnesium sulfate for AMI is 44 45 suboptimal, with 17% of patients with AMI given IV magnesium sulfate in 2015. The decrease 46 of rate was slowing down and stabilized around an unacceptably high level recently. 47 48 Furthermore, IV magnesium sulfate use is neither associated with particular hospital 49 50 characteristics, nor geographic/socio-economic regions. The findings highlighted the gaps in 51 52 performance and called for further researches on the causes. 53 54 Our work provides a critical evaluation of the ineffective therapy in healthcare across the 55 56 country, and implies that efforts aiming to more efficient mechanisms to translate evidence- 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 77 of 75 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from

1 2 3 based therapies into clinical practice in China are needed. China’s experiences could be highly 4 5 relevant to many low- and middle-income countries facing similar challenges over the world. We 6 7 believe this study will be of major interest to the readership of BMJ Open. 8 9 10 As the corresponding author, I take full responsibility for the content of this submission. I had 11 12 full access to all the data and final responsibility for the decision to submit for publication. All 13 14 authors contributed substantively to the manuscript and have approved the submission in its final 15 form. The manuscript has not been submitted elsewhere, or published elsewhere in whole or in 16 For peer review only 17 part in any language. 18 19 20 This project was partly supported by the National Key Research and Development Program from 21 22 the Ministry of Science and Technology of China, the Major Public Health Service Project from 23 the Ministry of Finance and National Health and Family Planning Commission of China, the 111 24 25 Project from the Ministry of Education of China. The funders had no role in study design, data 26 27 collection and analysis, decision to publish, or preparation of the manuscript. 28 29 We declare no relevant conflicts of interest. 30 31 32

We are grateful to you for considering our manuscript. http://bmjopen.bmj.com/ 33 34 35 36 37 38 39 Yours sincerely 40 on September 25, 2021 by guest. Protected copyright. 41 42 43 Dr. Xi Li 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from

Article Type: Original research

Date Submitted by the 20-Jan-2020 Author:

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1 2 3 Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai 4 Hospital, National Center for Cardiovascular Diseases, Chinese Academy 5 of Medical Sciences and Peking Union Medical College, Beijing, People's 6 Republic of China 7 Bai, Xueke; National Clinical Research Center of Cardiovascular Diseases, 8 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National 9 Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of 10 China 11 Krumholz, Harlan; Yale-New Haven Hospital Center for Outcomes 12 Research and Evaluation, 13 Li, Xi; National Clinical Research Center of Cardiovascular Diseases, 14 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National 15 Center for Cardiovascular Diseases, Chinese Academy of Medical 16 Sciences and Peking Union Medical College, Beijing, People's Republic of For peerChina review only 17 18 Primary Subject Cardiovascular medicine 19 Heading: 20 Secondary Subject Heading: Cardiovascular medicine 21 22 Keywords: acute myocardial infarction, Magnesium Sulfate, quality of health care 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 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 70

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1 2 3 Use of Intravenous Magnesium Sulfate among Patients with Acute Myocardial

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 Infarction in China from 2001 to 2015: China PEACE-Retrospective AMI Study 6 7 3 8 9 10 4 Running head: Magnesium Sulfate for AMI in China 11 12 5 13 14 6 Xianqiang Wang*, MD; Xue Du*, MD; Hao Yang; Emily Bucholz, MD PhD; Nicholas 15 16 7 Downing, MD; John A. Spertus, MD, MPH; Frederick A Masoudi, MD, MSPH; Jing Li, 17 18 8 MD, PhD; WenchiFor Guan, peer MD; Yan Gao; review Shuang Hu, PhD;only Xueke Bai, MS; Harlan M. 19 20 9 Krumholz#, MD SM; Xi Li#, PhD; for the China PEACE Collaborative Group (see 21 22 10 Appendix) 23 24 11 25 26 12 * Contribute equally 27 28 # Co-senior authors 29 13 30 31 14 32 33 15 National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory 34 35 16 of Cardiovascular Disease (XW, XD, HY, JL, WG, YG, SH, XB, XL), Fuwai Hospital, 36 37 17 National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences http://bmjopen.bmj.com/ 38 39 18 and Peking Union Medical College, Beijing, People's Republic of China; 40 41 19 Saint Luke’s Mid America Heart Institute and the University of Missouri-Kansas City 42 43 20 (JAS), Kansas City, Missouri, United States; 44 on September 25, 2021 by guest. Protected copyright. 45 21 Division of Cardiology (FAM), University of Colorado Anschutz Medical Campus, 46 47 22 Aurora, Colorado, United States; 48 49 50 23 Center for Outcomes Research and Evaluation (HMK, EB, ND), Yale-New Haven 51 52 24 Hospital, New Haven, Connecticut, United States; Section of Cardiovascular 53 54 25 Medicine (HMK), Robert Wood Johnson Clinical Scholars Program (HMK), 55 56 26 Department of Internal Medicine, Yale University School of Medicine, New Haven, 57 58 27 Connecticut, United States; Department of Health Policy and Management (HMK), 59 60 28 Yale School of Public Health, New Haven, Connecticut, United States.

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1 2 3 Correspondence: Dr Xi Li, National Clinical Research Center of Cardiovascular

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1 2 3 ABSTRACT

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 Objective 6 7 8 3 In 2001, Chinese guidelines for the care of acute myocardial infarction included a 9 10 4 new recommendation against the routine use of magnesium. We studied temporal 11 5 trends and institutional variation in the use of IV magnesium sulfate in nationally 12 13 6 representative samples of individuals hospitalized with AMI in China between 2001- 14 15 7 2015. 16 17 8 18 9 Methods For peer review only 19 20 10 In an observational study (China PEACE–Retrospective Study) of AMI care, we used 21 22 11 a 2-stage, random sampling strategy to create a nationally representative sample of 23 24 12 28,208 patients with AMI at 162 Chinese hospitals in 2001, 2006, 2011, and 2015. 25 26 13 The main outcome is use of IV magnesium sulfate over time. 27 28 29 14 Results 30 31 15 We identified 24,418 patients admitted for AMI, without hypokalemia, in the four 32 33 16 study years. Over time, there was a significant initial decrease in IV magnesium 34 35 17 sulfate use, from 32.1% in 2001 to 17.1% in 2015 (p< .001 for trend). The decline 36 37 18 was greater in the Eastern (from 33.3% to 16.5%) and Western (from 34.8% to http://bmjopen.bmj.com/ 38 39 19 17.2%) regions, as compared with the Central region (from 25.9% to 18.1%), with 40 41 20 little difference between rural and urban areas. The proportion of hospitals using IV 42 43 21 magnesium sulfate did not change over time (from 81.3% to 77.9%). The median 44 on September 25, 2021 by guest. Protected copyright. 45 22 odds ratios, representing hospital-level variation, were 6.03 in 2001, 3.86 in 2006, 46 47 48 23 4.26 in 2011, and 4.72 in 2015. IV magnesium sulfate use was associated with 49 50 24 cardiac arrest at admission and receipt of reperfusion therapy, but no hospital- 51 52 25 specific characteristics. 53 54 26 Conclusions 55 56 27 Despite recommendations against its use, IV magnesium sulfate is used in about 1 in 57 58 28 6 patients with AMI in China. Our findings highlight the need for more efficient 59 60 29 mechanisms to stop using ineffective therapies to improve patients’ outcomes and

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1 2 3 reduce medical waste.

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 6 7 3 8 9 10 4 Clinical Trial Registration 11 12 5 URL: https://www.clinicaltrials.gov. Unique identifier: NCT01624883 13 14 6 Keywords 15 16 7 acute myocardial infarction, Magnesium Sulfate, quality of health care 17 18 8 For peer review only 19 20 9 21 22 10 Strengths and limitations of this study 23 24 25 11  This is the first large nationally representative registry demonstrating IV 26 12 magnesium sulfate is still used in about 1 in 6 patients with AMI in China, 27 28 13 despite recommendations against its use since 2000s. 29 30 31 14  The study assessed the 15-year trend in the use of IV magnesium sulfate 32 15 among patient with AMI in China. 33 34 35 16  The study firstly reported both patients- and hospital-level resulted in the use 36

17 of IV magnesium sulfate use, which could provide more targeted information http://bmjopen.bmj.com/ 37 38 18 for efficient mechanisms to stop using this ineffective therapy. 39 40 41 19  The study adopted standardized procedures for abstraction of medical 42 20 records that ensure the reliability of our results in describing the use pattern 43 44 21 of magnesium sulfate in the real world. 45 on September 25, 2021 by guest. Protected copyright. 46 47 22  The very low prevalence of patients with some indications, such as 48 23 magnesium sulfate deficiency would have little influence on the reliability of 49 50 24 the results. 51 52 25 53 54 55 56 57 58 59 60

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1 2 3 INTRODUCTION

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 The history of intravenous (IV) magnesium sulfate use for acute myocardial infarction 6 7 3 (AMI) is convoluted. Once lauded in small, early trials as safe and highly effective,1-3 8 9 10 4 it was later demonstrated to be ineffective, and even harmful, in two large clinical 11 4 5 12 5 trials (MAGIC and ISIS-4) and in a subsequent meta-analysis. Beginning in the 13 14 6 early 2000s, AMI practice guidelines in the United States have specifically 15 16 7 recommended against its routine use (Class III, level of evidence: C).6 7 Similarly, 17 18 8 China publishedFor guidelines peer in 2001 recommendingreview against only the use of IV magnesium 19 20 9 sulfate in patients with AMI, except in the setting of hypomagnesemia or polymorphic 21 22 10 ventricular tachycardia.8 23 24 11 25 26 12 Although several studies have evaluated the introduction and uptake of new 27 28 therapies,9-11 few have examined de-adoption of ineffective therapy in clinical 29 13 30 12-14 31 14 practice. The de-adoption of therapy is particularly important because the 32 33 15 situation may involve greater resistance and barriers to discontinuing long-standing 34 35 16 practices than simply introducing new and promising therapies into practice.15 36 37 17 Characterizing the use of magnesium sulfate for AMI in clinical practice offers an http://bmjopen.bmj.com/ 38 39 18 opportunity to assess the speed with which providers stop using a therapy when new 40 41 19 evidence has overturned prior dogma. 42 43 20 44 on September 25, 2021 by guest. Protected copyright. 45 21 Accordingly, our objectives were to assess the trends and variation of regional and 46 47 22 hospital-level use of IV magnesium sulfate among patient with AMI using data from 48 49 50 23 the China PEACE Retrospective AMI Study between 2001 and 2015. These data, 51 52 24 from a nationally representative network of hospitals throughout China, provided a 53 54 25 unique opportunity to examine the trend for discontinuing routine IV magnesium 55 56 26 sulfate over time and to describe the variations across hospitals in its discontinuation. 57 58 27 59 60 28

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1 2 3 METHODS

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 Design Overview 6 7 3 The design and methods of the China PEACE-Retrospective AMI Study have been 8

9 16 10 4 previously published. In addition to a nationally representative sample of patients 11 12 5 admitted for AMI in China during 2001, 2006, and 2011 created in the China PEACE- 13 14 6 Retrospective AMI Study, we also included a more recent sample of patients 15 16 7 admitted in 2015 using the same two-stage random sampling process. Briefly, in the 17 18 8 first stage, we identifiedFor hospitalspeer using review a simple random only sampling procedure within 19 20 9 5 economic-geographic regions: Eastern rural, Central rural, Western rural, Eastern 21 22 10 urban, and Central/Western urban. We stratified on both location and urban-rural 23 24 11 classifications because economic development and clinical capacities differed across 25 26 12 these categories. We sampled representative hospitals from 2011 to reflect current 27 28 practices and used the same hospitals for the 2006, 2001, and 2015 so as to 29 13 30 31 14 describe temporal trends. In the second stage, we sampled AMI cases from hospital 32 33 15 databases in 2001, 2006, 2011, and 2015 using random sampling procedures. 34 35 16 36 37 17 Trained personnel at the national coordinating centers abstracted data from the http://bmjopen.bmj.com/ 38 39 18 medical records using standardized data definitions. Data abstraction quality was 40 41 19 rigorously monitored by randomly auditing 5% of the medical records, in a process 42 43 20 that ensured that the overall variable accuracy exceeded 98%.16 We also obtained 44 on September 25, 2021 by guest. Protected copyright. 45 21 information on the organizational learning culture of hospital in 2013 through 46 47 22 questionnaires completed by the director and a physician of the Cardiology 48 49 17 50 23 Department in each participating hospital (see Appendix). 51 52 24 53 54 25 The Ethics Committee at the National Center for Cardiovascular Diseases approved 55 56 26 the study. All collaborating hospitals either accepted central ethics approval or 57 58 27 obtained local ethics approval by their ethics committees. Given the retrospective 59 60 28 nature of the data and the lack of personal identifiers, patient-level consent was not

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1 2 3 required. The study was registered with ClinicalTrials.gov (NCT01624883).

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1 2 3 (LOS-27, an abbreviated version of the original Garvin et al. Learning Organization

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 Survey).18 The LOS-27 consists of 27 questions, grouped into 7 domains of 6 7 3 organizational learning characteristics, including supportive learning environment, 8 9 10 4 time for reflection, leadership that reinforces learning, experimentation, training, 11 12 5 knowledge acquisition, and performance monitoring. 13 14 6 15 16 7 Statistical analysis 17 18 8 To examine theFor trends at peer both the population review and hospital only levels across different 19 20 9 study periods, p-values for trends were reported using the Cochran–Armitage test. 21 22 10 We described the hospital-level distribution of the IV magnesium sulfate use among 23 24 11 the hospitals with at least 10 patients with AMI in the study years. To further 25 26 12 understand the hospital-level variation in IV magnesium sulfate use, we quantified 27 28 inter-hospital variation using the median odds ratio (MOR), by constructing 29 13 30 31 14 generalized estimating equations in 2001, 2006, 2011, and 2015, respectively. MOR 32 33 15 represents the average (median) OR for receiving IV magnesium sulfate for 2 AMI 34 35 16 patients with similar clinical characteristics admitted to 2 randomly selected hospitals. 36 37 17 http://bmjopen.bmj.com/ 38 39 18 To understand the most current pattern in IV magnesium sulfate use, we constructed 40 41 19 multivariable models using the data from 2015, which also adopted generalized 42 43 20 estimating equations to account for the clustering of patients within hospitals. Factors 44 on September 25, 2021 by guest. Protected copyright. 45 21 were selected based on clinical judgment and literature review,10,11 including patient 46 47 and hospital characteristics. All covariates showed in Table 1, except those with 48 22 49 50 23 frequencies below 1%, were included in the multivariable model. We transformed 51 52 24 continuous variables (e.g. age and heart rate) into categorical variables using 53 54 25 clinically meaningful cut-off values, and then created dummy variables. From the 55 56 26 multivariable model in 2015, we then computed risk-standardized rates for each 57 58 27 hospital separately. The risk-standardized rate was calculated as the ratio of 59 60 28 observed to predicted outcomes, multiplied by the overall unadjusted rate, a form of

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1 2 3 indirect standardization. Regarding the different dosage of IV magnesium sulfate, we

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 conducted a sensitivity analysis to compare patients receiving multiple doses to 6 7 3 those receiving a single dose of or no IV magnesium sulfate. 8 9 10 4 11 12 5 To compare the outcomes between patients with and without IV magnesium sulfate, 13 14 6 we applied propensity score matching to adjust differences in observed 15 16 7 characteristics between them. We obtained the log odds of the probability that 17 18 8 patients receivedFor IV magnesium peer sulfate review with modeling onlya function of all the variables 19 20 9 in Table1. Then we performed a one-to-one no replacement match between the two 21 22 10 groups based on the estimated propensity score. The no IV magnesium sulfate 23 24 11 patients was matched if patient had the closest score with a randomly selected IV 25 26 12 magnesium sulfate patient, and were considered eligible to match if the estimated 27 28 logit within 0.6 standard deviation of the selected IV magnesium sulfate patient. This 29 13 30 31 14 matching interval has been shown to eliminate approximately 90% of the bias in 32 19 33 15 observed confounders (Appendix). 34 35 16 36 37 17 For the questionnaire with LOS-27 (Appendix), we analyzed the responses at the http://bmjopen.bmj.com/ 38 39 18 hospital level by calculating the average of the 2 responses to each question. 40 41 19 Responses were categorized as positive if they were 5 on a 7-point scale or 4 on a 42 43 20 5-point scale. We then calculated the positive response rate at each hospital as the 44 45 on September 25, 2021 by guest. Protected copyright. 46 21 proportion of questions that had a positive response by the hospital, and 47 48 22 demonstrated the correlations between positive response rate and risk-standardize 49 50 23 rate of IV magnesium sulfate use in 2015, as well as the reduction in IV magnesium 51 52 24 sulfate use from 2011 to 2015. 53 54 25 55 56 26 All comparisons were two-sided, with statistical significance defined as p less 57 58 27 than .05. Statistical analysis was done with SAS software, version 9.4, and R 59 60 28 software, version 3.3.1.

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1 2 3

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 Patient and Public Involvement statement 6 7 3 Patients or public were not involved in the development of the study protocol. 8 9 10 4 11 12 5 RESULTS 13 14 6 Study population 15 16 7 We identified 28,208 patients with AMI in 2001, 2006, 2011 and 2015 admitted to 17 18 8 162 hospitals. AfterFor excluding peer patients review with hypokalemia only (<3.5 mmol/L, n= 3,790), 19 20 9 24,418 patients remained, including 2,073 in 2001, 3,888 in 2006, 8,117 in 2011 and 21 22 10 10,340 in 2015 (Figure 1). Almost half (41.2%) of the patients were hospitalized in 23 24 11 rural areas. In the study population, the average age was 65.1±12.7 years, 29.7% 25 26 27 12 were female, almost three quarters had at least one cardiac risk factors 28 29 13 (hypertension, diabetes, dyslipidemia or smoking), and about 10% had has a prior 30 31 14 myocardial infarction or ischemic stroke (Table 1). 32 33 15 34 35 16 Temporal trends and regional variations in IV magnesium sulfate use 36 http://bmjopen.bmj.com/ 37 17 Over time, there was a significant initial decrease in the use of IV magnesium sulfate, 38 39 18 from 32.1% (665) in 2001 to 18.4% (715) in 2006, 15.4% (1,251) in 2011 and 17.1% 40 41 19 (1,763) in 2015 (p< .001 for trend) (Figure 2). There was significant variation in the 42 43 44 20 temporal trends of use of IV magnesium sulfate across the five strata (p< .001 for 45 on September 25, 2021 by guest. Protected copyright. 46 21 interaction). In general, the decline was greater in the Eastern region [16.8% (from 47 48 22 33.3% in 2001 to 16.5% in 2015), p< .001] and Western region [16.6% (from 34.8% 49 50 23 in 2001 to 17.2% in 2015), p< .001], compared with the Central regions [7.8% (from 51 52 24 25.9% in 2001 to 18.1% in 2015), p< .001]. There was a more modest difference 53 54 25 between rural areas [16.3% (from 31.6% to 15.3%), p< .001] than in urban areas 55 56 26 [13.9% (from 32.4% to 18.5%), p< .001]. No significant association was found 57 58 27 between the positive response rate of LOS-27 in 2013 and the hospital-level 59 60

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1 2 3 reduction in IV magnesium sulfate use from 2011 to 2015 (R2=0.011, p= .237)

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 (Appendix). 6 7 3 8 9 10 4 Hospital-level distributions in IV magnesium sulfate use 11 12 5 We examined hospital-level rates of IV magnesium sulfate use among hospitals with 13 14 6 10 or more cases per year, and observed a downward trend in the median, from 15 16 7 17.4% in 2001, 9.1% in 2006, 8.0% in 2011 to 10.7% in 2015 (Figure 3). However, 17 18 8 the proportion ofFor hospitals peer still using magnesiumreview sulfate only were 81.3% in 2001, 84.8% 19 20 9 in 2006, 76.6% in 2011, and 77.9% in 2015, with no significant decline (p for trend 21 22 10 = .26). Even in 2015, a quarter of hospitals had rates of IV magnesium sulfate use 23 24 11 exceeding 25%. The MORs (95% CI) of each year characterized similar degrees of 25 26 12 hospital-level variation (6.03 (3.93-8.52) in 2001, 3.86 (3.00-.4.77) in 2006, 4.26 27 28 (3.38-5.20) in 2011, and 4.72 (3.70-5.83) in 2015). 29 13 30 31 14 32 33 15 Patient and hospital characteristics associated with IV magnesium sulfate use 34 35 16 In univariate analysis, patients receiving IV magnesium sulfate were more likely to 36 37 17 not have diabetes, dyslipidemia or a prior revascularization, were more likely to have http://bmjopen.bmj.com/ 38 39 18 had a prior ischemic stroke or cardiac arrest at presentation. They were more likely 40 41 19 to receive reperfusion therapy, be at urban hospital, or be in Central or Western 42 43 20 regions (Table 1). In the multivariable model, presence of cardiac arrest at admission 44 on September 25, 2021 by guest. Protected copyright. 45 21 (OR 3.38, 95% CI 2.50-5.82, P< .001), receipt of aspirin within 24h (1.43(1.22-1.67), 46 47 22 statin use (1.33(1.13-1.57), reperfusion therapy (1.67 (1.35-1.90) for fibrinolytic 48 49 50 23 therapy, 1.69 (1.44-1.98) for primary PCI, both P< .0001), and onset of heart failure 51 52 24 (OR 1.69, 95% CI 1.34-2.09, P< .001) were positively associated with IV magnesium 53 54 25 sulfate use (Appendix). No significant difference was identified across the teaching 55 56 26 status, economic geographic region and rural/urban of hospitals (Table 1). The risk- 57 58 27 standardized rate of IV magnesium sulfate use in 2015 was not associated with the 59 60 28 positive response rate of LOS-27 (R2=0.027, p= .04) (Appendix).

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1 2 3 In-hospital outcomes of patients with and without IV magnesium sulfate use

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 In the patients treated with IV magnesium sulfate, the crude rates of in-hospital death 6 7 3 (7.5% vs. 6.4%) (Figure 4), in-hospital death or treatment withdraw (10.8% vs. 8 9 10 4 9.5%), and in-hospital composite of major complications (22.0% vs. 17.6%) were 11 12 5 higher than patients without IV magnesium sulfate therapy (P< .01 for all). After 13 14 6 adjusted for hospital characteristics, patient risk profiles, medication and reperfusion 15 16 7 therapies, using propensity score matching, the in-hospital death rates were not 17 18 8 significantly differentFor between peer the treated review and non-treated only patients (OR 1.13, 95% CI 19 20 9 0.96-1.33, P= .15). However, the patients treated with IV magnesium sulfate had still 21 22 10 higher risk for in- hospital death (OR 1.18,95%CI 1.03-1.36, P=. 01), in-hospital 23 24 11 death or treatment withdraw (OR 1.24, 95% CI 1.09-1.41, P= .001), and in- hospital 25 26 12 composite of major complications (OR 1.32, 95% CI 1.19-1.47, P< .001). 27 28 29 13 30 31 14 Different Dose of IV magnesium sulfate 32 33 15 We hypothesized that that magnesium sulfate prescribed more than once was more 34 35 16 likely to be a routine administration than the single dose that is commonly used for 36 37 17 repletion or arrhythmias. Thus, we conducted a sensitivity analysis focusing on http://bmjopen.bmj.com/ 38 39 18 multiple doses. The sensitivity analysis showed that there was also a significant 40 41 19 decrease in the multiple doses of IV magnesium sulfate, from 28.9% in 2001 to 42 43 20 14.5% in 2006, 10.9% in 2011 and 11.31% in 2015 (p< .001 for trend). Nearly 44 on September 25, 2021 by guest. Protected copyright. 45 21 identical predictors of IV magnesium sulfate use were found when we compared 46 47 22 patients receiving multiple doses to those without IV magnesium sulfate (Appendix). 48 49 50 23 51 52 24 DISCUSSION 53 54 25 In this large nationally representative study, we found that despite an initial decline in 55 56 26 the use of IV magnesium sulfate for patients with AMI in China after 2001, about 1 in 57 58 27 6 patients continued to be treated with it through 2015. Furthermore, there was 59 60 28 substantial variation in the use of IV magnesium sulfate use across hospitals. No

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1 2 3 hospital characteristics were associated with IV magnesium sulfate use after

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 adjusting for patient factors, including cardiac arrest and use of reperfusion therapy 6 7 3 during hospitalization. 8 9 10 4 11 12 5 Our study is the first, to our knowledge, to characterize the rate of de-adoption of 13 14 6 magnesium sulfate in patients with AMI in China. The only real-word study on the 15 16 7 use of magnesium sulfate to treat AMI, which was based on data from the National 17 18 8 Registry of MyocardialFor Infarction peer (NRMI-2) review in the United only States, found that the use 19 20 9 rate of magnesium sulfate in patients within first 24 hours after AMI was 5.1% in 21 22 10 2001 – 5 years after the US guideline recommended against the use of magnesium 23 24 11 sulfate.20 Questionnaire for chief cardiologist from 2500 hospital in China in 1998 25 26 12 revealed that 47% of physician would prescribe magnesium sulfate for patients with 27 28 AMI.21 In contrast in 2015, three-fold more Chinese patients with AMI were receiving 29 13 30 31 14 magnesium sulfate. This is congruent with a survey among cardiologists in 2012, 32 33 15 where over one fifth reported that they were routinely using magnesium sulfate in 34 35 16 patients with ACS.22 36 37 17 http://bmjopen.bmj.com/ 38 39 18 Several patient characteristics were identified to be associated with the use of IV 40 41 19 magnesium sulfate for AMI. It was plausible that the presence of cardiac arrest or 42 43 20 reperfusion therapy may spur some physicians to use magnesium sulfate to prevent 44 on September 25, 2021 by guest. Protected copyright. 45 21 arrhythmias, according to prior studies in both China and other countries.1 6 23-26 46 47 These explanations, even though not recommended by the guidelines, highlighted 48 22 49 50 23 the gaps in physicians’ practice and highlights the needs for targeted education in the 51 52 24 future. 53 54 25 55 56 26 The hospital-level and regional variations in IV magnesium sulfate highlights the 57 58 27 marked variability with which different hospitals adopted new evidence about the lack 59 60 28 of benefit from IV magnesium sulfate use. On the one hand, magnesium sulfate use

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1 2 3 in 2015 was neither associated with hospital-specific characteristics, nor different

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 across geographic or socio-economic regions. The teaching status or tertiary level 6 7 3 did not translate into the better performance in this measure, which underscores the 8 9 10 4 widespread need for continued education and evaluation of clinical practice. On the 11 12 5 other hand, the regional variation in de-adoption of magnesium sulfate during the 15- 13 14 6 year period seemed not directly related to the regional socio-economic development 15 16 7 status that might be assumed to affect the resources available for acquiring and 17 18 8 implementing guidelineFor recommendation.peer review Moreover, no only evidence connects 19 20 9 organizational learning culture with high performance, even much has been observed 21 22 10 in studies of US hospitals.27 Given our findings, more research is needed to better 23 24 11 understand current practice patterns that cause some hospitals to still use ineffective 25 26 12 therapies. 27 28 29 13 30 31 14 Our findings raise several questions about the dissemination and implementation of 32 33 15 evidence and guidelines in China, particularly regarding education for physicians 34 35 16 when long-standing therapies are demonstrated to be non-beneficial, and need to be 36 37 17 de-adopted. We hypothesized that several factors may explain why the rate of http://bmjopen.bmj.com/ 38 39 18 magnesium sulfate use has remained relatively high in China. First, few actions have 40 41 19 been taken to disseminate guidelines – after China published the guideline against IV 42 43 20 magnesium sulfate for AMI in 2001,8 the textbook used in all Chinese medical 44 on September 25, 2021 by guest. Protected copyright. 45 21 colleges had not stopped recommending IV magnesium sulfate use in patients with 46 47 22 AMI until 2009.28 Second, China’s hospital system is short for mechanisms to 48 49 50 23 facilitate the implementation of guideline recommendations, and systematic 51 52 24 approaches for monitoring the performance of hospitals and physicians in following 53 54 25 the guidelines are lacking in China.29 55 56 26 57 58 27 The successful de-adoption of non-beneficial or potentially harmful therapies for 59 60 28 corresponding disease, which could reduce costs and potentially prevent

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1 2 3 complications, requires more than increased efforts from the part of guideline

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 developers.12 After the dissemination of the guideline, more complicated issues need 6 7 3 to be addressed, including how to develop tools reminding and alerting physicians 8 9 10 4 when non-recommended therapies are ordered, how to establish a system to report 11 12 5 feedback periodically on the appropriateness of treatment by practitioners and 13 14 6 hospitals, how to design an accountability-oriented mechanism to prohibit ineffective 15 16 7 regimen being prescribed, etc.30 These issues could only be properly addressed 17 18 8 through collaborationsFor with peer researchers, review educators, policymakers only and other 19 20 9 stakeholders.31 32 21 22 10 23 24 11 This study has several limitations that warrant consideration. First, we could not 25 26 12 exclude patients with some indications, such as hypomagnesaemia and episodes of 27 28 Torsade de pointes. However, we estimate that the influence is relatively small given 29 13 30 33 34 31 14 low prevalence of these conditions previously reported. Second, we did not have 32 33 15 the ability to prospectively ask clinicians why they were prescribing IV magnesium 34 35 16 sulfate, which limited our capability to gain better understanding of the use pattern 36 37 17 and influencing factors. Third, our data were acquired retrospectively through http://bmjopen.bmj.com/ 38 39 18 medical record abstraction. Thus, the quality of our data depends on the accuracy 40 41 19 and completeness of prior documentation and abstraction. Nevertheless, the 42 43 20 standardized procedures for abstraction of medical records ensure the reliability of 44 on September 25, 2021 by guest. Protected copyright. 45 21 our results in describing the use pattern of magnesium sulfate in the real world. Also, 46 47 22 we analyzed the data at the hospital level and were not able to determine whether 48 49 50 23 the observed patterns were due to only a few physicians, or were common 51 52 24 throughout a hospital’s staff. Finally, residual confounding of measured or 53 54 25 unmeasured variables might affect the observed results about in-hospital outcomes 55 56 26 of patients with and without IV magnesium sulfate use. 57 58 27 59 60 28 In conclusion, the de-adoption of magnesium sulfate for patients with AMI is

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1 2 3 suboptimal, moreover, the decrease of rate was slowing down recently, steady at an

1 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 2 unacceptably high level. Our findings highlight the need for more efficient 6 7 3 mechanisms to translate evidence-based therapies into clinical practice in China to 8 9 10 4 improve patients’ outcomes and reduce medical waste. 11 12 5 13 14 6 ACKNOWLEDGMENTS 15 16 7 We appreciate the multiple contributions made by study teams at National Clinical 17 18 8 Research CenterFor of Cardiovascular peer Diseasesreview and Yale-New only Haven Hospital Center 19 20 9 for Outcomes Research and Evaluation in study design and operations, particularly 21 22 10 the data collection by Yi Pi, Jiamin Liu, Wuhanbilige Hundei, Haibo Zhang, Lihua 23 24 11 Zhang, Wenchi Guan, Xiaofang Yan, Yuan Yu, Xiqian Huo, Xin Zheng, and Yuanlin 25 26 12 Guo. We appreciate the editing by Aoxi Tian. We are grateful for the support 27 28 provided by the Chinese government. 29 13 30 31 14 32 33 15 CONTRIBUTORS 34 35 16 XL, JL and HMK conceived the China PEACE study and take responsibility for all 36 37 17 aspects of it. XW, XD, JL, FAM, JAS, JL, HMK and XL designed the study. XW and http://bmjopen.bmj.com/ 38 39 18 XD wrote the first draft of the article, with further contributions from HY, EB, ND, JAS, 40 41 19 FAM, JL, WG, HMK and XL. SH, YG and XB did statistical analysis. XL had full 42 43 20 access to all the data in the study and take responsibility for the integrity of the data 44 on September 25, 2021 by guest. Protected copyright. 45 21 and the accuracy of the data analysis. All authors interpreted data and approved the 46 47 22 final version of the article. 48 49 50 23 51 52 24 DISCLOSURES 53 54 25 There are no relevant conflicts of interest. 55 56 26 57 58 27 FUNDING 59 60 28 This project was partly supported by the National Key Research and Development

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1 2 3 ， 1 Program (2017YFC1310803, 2017YFC1310801 2015BAI12B01) from the Ministry BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 6 2 of Science and Technology of China, the Major Public Health Service Project from 7 8 3 the Ministry of Finance and National Health and Family Planning Commission of 9 10 4 China, the 111 Project from the Ministry of Education of China (B16005). Dr. 11 12 5 Krumholz is supported by grant U01 HL105270-05 (Center for Cardiovascular 13 14 6 Outcomes Research at Yale University). The sponsors had no role in the conduct of 15 16 7 the study; in the collection, management, analysis, and interpretation of the data; or 17 18 8 in the preparationFor or approval peer of the manuscript.review only 19 20 9 21 22 10 DATA SHARING STATEMENT 23 24 25 11 Extra data is available by emailing [email protected]. 26 12 27 28 13 29 30 31 14 32 33 15 REFERENCE 34 35 16 1. Horner SM. Efficacy of intravenous magnesium in acute myocardial infarction 36 37 17 in reducing arrhythmias and mortality. Meta-analysis of magnesium in http://bmjopen.bmj.com/ 38 39 18 acute myocardial infarction. Circulation 1992;86(3):774-9. 40 19 2. Teo KK, Yusuf S, Collins R, et al. Effects of intravenous magnesium in suspected 41 42 20 acute myocardial infarction: overview of randomised trials. BMJ (Clinical 43 44 21 research ed) 1991;303(6816):1499-503. 45 on September 25, 2021 by guest. Protected copyright. 46 22 3. Thogersen AM, Johnson O, Wester PO. Effects of magnesium infusion on 47 23 thrombolytic and non-thrombolytic treated patients with acute 48 49 24 myocardial infarction. International journal of cardiology 1993;39(1):13- 50 51 25 22. 52 53 26 4. ISIS-4: a randomised factorial trial assessing early oral captopril, oral 54 55 27 mononitrate, and intravenous magnesium sulphate in 58,050 patients 56 28 with suspected acute myocardial infarction. ISIS-4 (Fourth International 57 58 29 Study of Infarct Survival) Collaborative Group. Lancet 59 60 30 1995;345(8951):669-85.

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1 2 3 4 1 5. Early administration of intravenous magnesium to high-risk patients with BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 2 acute myocardial infarction in the Magnesium in Coronaries (MAGIC) 6 7 3 Trial: a randomised controlled trial. Lancet 2002;360(9341):1189-96. 8 9 4 6. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the 10 11 5 management of patients with ST-elevation myocardial infarction-- 12 6 executive summary: a report of the American College of 13 14 7 Cardiology/American Heart Association Task Force on Practice 15 16 8 Guidelines (Writing Committee to Revise the 1999 Guidelines for the 17 18 9 ManagementFor of peer Patients With review Acute Myocardial only Infarction). Circulation 19 10 2004;110(5):588-636. 20 21 11 7. Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the 22 23 12 management of patients with acute myocardial infarction. A report of the 24 25 13 American College of Cardiology/American Heart Association Task Force 26 27 14 on Practice Guidelines (Committee on Management of Acute Myocardial 28 15 Infarction). J Am Coll Cardiol 1996;28(5):1328-428. 29 30 16 8. China Society of Cardiology of Chinese Medical Association EBoCJoC. Guideline 31 32 17 for diagnosis and treatment of patients with acute myocardial infarction. 33 34 18 Chinese Circulation Journal 2001;16(6):407-22. 35 19 9. Gambassi G, Forman DE, Lapane KL, et al. Management of heart failure among 36 37 20 very old persons living in long-term care: has the voice of trials spread? http://bmjopen.bmj.com/ 38 39 21 The SAGE Study Group. Am Heart J 2000;139(1 Pt 1):85-93. 40 41 22 10. Kim N, Gross C, Curtis J, et al. The impact of clinical trials on the use of 42 23 hormone replacement therapy. A population-based study. Journal of 43 44 24 general internal medicine 2005;20(11):1026-31. 45 on September 25, 2021 by guest. Protected copyright. 46 25 11. Stafford RS, Furberg CD, Finkelstein SN, et al. Impact of clinical trial results on 47 48 26 national trends in alpha-blocker prescribing, 1996-2002. Jama 49 27 2004;291(1):54-62. 50 51 28 12. Hauptman PJ, Schnitzler MA, Swindle J, et al. Use of nesiritide before and after 52 53 29 publications suggesting drug-related risks in patients with acute 54 55 30 decompensated heart failure. Jama 2006;296(15):1877-84. 56 31 13. Sauro K, Bagshaw SM, Niven D, et al. Barriers and facilitators to adopting high 57 58 32 value practices and de-adopting low value practices in Canadian intensive 59 60 33 care units: a multimethod study. BMJ open 2019;9(3):e024159.

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1 2 3 4 1 14. Niven DJ, McCormick TJ, Straus SE, et al. Identifying low-value clinical BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 2 practices in critical care medicine: protocol for a scoping review. BMJ 6 7 3 open 2015;5(10):e008244. 8 9 4 15. Niven DJ, Rubenfeld GD, Kramer AA, et al. Effect of published scientific 10 11 5 evidence on glycemic control in adult intensive care units. JAMA Intern 12 6 Med 2015;175(5):801-9. 13 14 7 16. Dharmarajan K, Li J, Li X, et al. The China Patient-Centered Evaluative 15 16 8 Assessment of Cardiac Events (China PEACE) retrospective study of acute 17 18 9 myocardialFor infarction: peer study review design. Circulation only Cardiovascular quality 19 10 and outcomes 2013;6(6):732-40. 20 21 11 17. Yin ES, Downing NS, Li X, et al. Organizational culture in cardiovascular care 22 23 12 in Chinese hospitals: a descriptive cross-sectional study. Bmc Health 24 25 13 Services Research 2015;15(1):569. 26 27 14 18. Singer SJ, Moore SC, Meterko M, et al. Development of a short-form Learning 28 15 Organization Survey: the LOS-27. Med Care Res Rev 2012;69(4):432-59. 29 30 16 19. Xing SG, Rosenbaum PR. Comparison of Multivariate Matching Methods: 31 32 17 Structures, Distances, and Algorithms. Journal of Computational & 33 34 18 Graphical Statistics 1993;2(4):405-20. 35 19 20. Ziegelstein RC, Hilbe JM, French WJ, et al. Magnesium use in the treatment of 36 37 20 acute myocardial infarction in the United States (observations from the http://bmjopen.bmj.com/ 38 39 21 Second National Registry of Myocardial Infarction). Am J Cardiol 40 41 22 2001;87(1):7-10. 42 23 21. LX. J, ZM. C, JX. X, et al. [Suvery of hospital of myocardial infarction in China]. 43 44 24 Linchuang XIn Xue Guan Bing Za Zhi, 2002 (9):417-20. 45 on September 25, 2021 by guest. Protected copyright. 46 25 22. Yiping Chen LJ, Qiuli Zhang, Xiaoshuai Wei, Xi Li, Margaret Smith, Zhengming 47 48 26 Chen. Doctor-reported hospital management of acute coronary syndrome 49 27 in China: A nationwide survey of 1029 hospitals in 30 provinces. World 50 51 28 Journal of Cardiovascular Diseases 2012;2:168-76. 52 53 29 23. Abraham AS, Rosenmann D, Kramer M, et al. Magnesium in the prevention of 54 55 30 lethal arrhythmias in acute myocardial infarction. Arch Intern Med 56 31 1987;147(4):753-5. 57 58 32 24. Rapaport E. Guidelines for the acute coronary syndromes. Current cardiology 59 60 33 reports 2001;3(4):289-98.

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1 2 3 4 1 25. Raghu C, Peddeswara Rao P, Seshagiri Rao D. Protective effect of intravenous BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 2 magnesium in acute myocardial infarction following thrombolytic 6 7 3 therapy. Int J Cardiol 1999;71(3):209-15. 8 9 4 26. Zhou H, Sun M. Suppresion of thrombolysis-induced reperfusion arrhythmias 10 11 5 in acute myocardial infarction by magnesium sulfate. Journal of Clinical 12 6 Cardiology 2000;16(4):156-58. 13 14 7 27. Bradley EH, Curry LA, Spatz ES, et al. Hospital strategies for reducing risk- 15 16 8 standardized mortality rates in acute myocardial infarction. Ann Intern 17 18 9 Med 2012;For156(9):618-26. peer review only 19 10 28. Lu Z, Zhong N. Internal Medicine (The seventh edition). Beijing: People's 20 21 11 Medical Publishing House, 2009. 22 23 12 29. Jiang L, Krumholz HM, Li X, et al. Achieving best outcomes for patients with 24 25 13 cardiovascular disease in China by enhancing the quality of medical care 26 27 14 and establishing a learning health-care system. Lancet 28 15 2015;386(10002):1493-505. 29 30 16 30. Niven DJ, Mrklas KJ, Holodinsky JK, et al. Towards understanding the de- 31 32 17 adoption of low-value clinical practices: a scoping review. BMC medicine 33 34 18 2015;13:255. 35 19 31. Carrese JA, Malek J, Watson K, et al. The essential role of medical ethics 36 37 20 education in achieving professionalism: the Romanell Report. Academic http://bmjopen.bmj.com/ 38 39 21 medicine : journal of the Association of American Medical Colleges 40 41 22 2015;90(6):744-52. 42 23 32. Grimshaw J, Eccles M, Tetroe J. Implementing clinical guidelines: current 43 44 24 evidence and future implications. The Journal of continuing education in 45 on September 25, 2021 by guest. Protected copyright. 46 25 the health professions 2004;24 Suppl 1:S31-7. 47 48 26 33. Kafka H, Langevin L, Armstrong PW. Serum magnesium and potassium in 49 27 acute myocardial infarction. Influence on ventricular arrhythmias. Arch 50 51 28 Intern Med 1987;147(3):465-9. 52 53 29 34. Romano TJ. Serum magnesium levels may not indicate low tissue magnesium 54 55 30 levels. Archives of internal medicine 1997;157(4):460. 56 57 58 59 60

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1 2 3 Table 1. Baseline characteristics of using IV magnesium sulfate 4 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 Non- Characteristics Overall Use N(%) P value 6 Use(%) 7 Patient characteristics 8 9 Age 0.234 10 <55 5262(21.5) 938(21.3) 4324(21.6) 11 55-64 5821(23.8) 1072(24.4) 4749(23.7) 12 65-74 6989(28.6) 1290(29.4) 5699(28.5) 13 14 >=75 6346(26.0) 1094(24.9) 5252(26.2) 15 Gender 0.144 16 Female 7257(29.7) 1346(30.6) 5911(29.5) 17 Male 17161(70.3) 3048(69.4) 14113(70.5) 18 For peer review only 19 Hypertension 12551(51.4) 2247(51.1) 10304(51.5) 0.7 20 Diabetes 4758(19.5) 768(17.5) 3990(19.9) <.001 21 Dyslipidemia 1588(6.5) 235(5.3) 1353(6.8) <.001 22 Currently smoking 8084(33.1) 1496(34.0) 6588(32.9) 0.144 23 Prior ischemic stroke 2706(11.1) 546(12.4) 2160(10.8) 0.002 24 Prior myocardial infarction 2504(10.3) 416(9.5) 2088(10.4) 0.057 25 Prior CABG/PCI 713(2.9) 104(2.4) 609(3.0) 0.016 26 Chest discomfort 22211(91) 4021(91.5) 18190(90.8) 0.161 27 Left branch block at presentation 342(1.4) 65(1.5) 277(1.4) 0.624 28 Cardiac arrest at presentation 271(1.1) 81(1.8) 190(0.9) <.001 29 Cardiogenic shock at presentation 1436(5.9) 279(6.3) 1157(5.8) 0.145 30 31 Acute stroke at presentation 530(2.2) 77(1.8) 453(2.3) 0.036 32 Heart rate at presentation, bpm 0.052 33 <50 1019(4.2) 177(4) 842(4.2) 34 50-110 21760(89.1) 3886(88.4) 17874(89.3) 35 >110 1639(6.7) 331(7.5) 1308(6.5) 36 37 SBP at presentation, mmHg 0.004 http://bmjopen.bmj.com/ 38 <120 8181(33.5) 1565(35.6) 6616(33.0) 39 120-139 7534(30.9) 1299(29.6) 6235(31.1) 40 140-159 5041(20.6) 913(20.8) 4128(20.6) 41 42 >=160 3662(15.0) 617(14.0) 3045(15.2) 43 New onset of heart failure 2506(10.3) 569(12.9) 1937(9.7) <0.001 44 Medication within 24-hour 45 Aspirin 13742(56.3) 2688(61.2) 11054(55.2) <0.001 on September 25, 2021 by guest. Protected copyright. 46 ACE inhibitors or angiotensin receptor 13662(56) 2541(57.8) 11121(55.5) 0.006 47 blockers 48 β-blockers 10051(41.2) 1768(40.2) 8283(41.4) 0.169 49 Clopidogrel 10572(43.3) 1845(42) 8727(43.6) 0.054 50 Statins 13031(53.4) 2398(54.6) 10633(53.1) 0.076 51 Reperfusion therapies <.001 52 53 No reperfusion 18720(76.7) 3130(71.2) 15590(77.9) 54 Fibrinolytic therapy 3136(12.8) 746(17.0) 2390(11.9) 55 Primary PCI 2562(10.5) 518(11.8) 2044(10.2) 56 Hospital characteristics 57 58 Teaching hospital 19081(78.1) 3462(78.8) 15619(78.0) 0.252 59 PCI-capable hospital 15876(65.0) 2768(63.0) 13108(65.5) 0.002 60 Hospital level 0.075

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1 2 3

Secondary or lower 9045(37.0) 1576(35.9) 7469(37.3) BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 5 Tertiary hospital 15373(63.0) 2818(64.1) 12555(62.7) 6 Economic geographic region 0.01 7 Eastern 13614(55.8) 2360(53.7) 11254(56.2) 8 Central 5886(24.1) 1115(25.4) 4771(23.8) 9 10 Western 4918(20.1) 919(20.9) 3999(20.0) 11 Urban/Rural 0.003 12 Rural 10064(41.2) 1724(39.2) 8340(41.7) 13 Urban 14354(58.8) 2670(60.8) 11684(58.3) 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 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 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 Figure 1 26 27 338x190mm (96 x 96 DPI) 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 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 70 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. 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 Figure 2 29 30 179x119mm (300 x 300 DPI) 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 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 70 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. 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 Figure 3 40 127x127mm (300 x 300 DPI) 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 Page 29 of 70 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. 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 Figure 4 23 24 249x119mm (300 x 300 DPI) 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 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30 of 70

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1 2 3 4 Hospital of Shangqiu Shi, Guiyu Huang, JianjunPan,QingliangCai,Qianying Wang; The General BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 Hospital of Yongzhou, Hunan Province, MingliLv; The people's hospital of Wuchuan, Yuanming Yi, 7 8 Xuelian Deng; The People's Hospital of Yuanling, Wenhua Chen, RongCai; The People's Hospital of 9 10 Zhijiang City, Bing Zhang; The Second Affiliated Hospital of Harbin Medical University, Bo Yu, 11 12 Yousheng Xu, Zhengqiu Wang; The Second Affiliated Hospital of Kunming Medical University, Jun 13 14 Shu, Ge Zhang, Kai Li; The Second Central Hospital of Baoding City, Guang Ma, PuxiaSuo; The 15 16 Second People's Hospital of Liaoyuan City, Aimin Zhang, Yongfen Kang; Tianjin Medical University 17 18 General Hospital, ZheForng Wan,Yuemin peer Sun, Boreview Bian; Tibet Autonomous only Region People's Hospital, 19 20 Xuejun Hu, DawaCiren; Tongchuan Mining Bureau Central Hospital, GuojiongJia, Jieli Pan; 21 22 Tongliang County People's Hospital, Guofu Li, Hongliang Zhang, Longliang Zhan; Tongliao City 23 24 Horqin District First People's Hospital, Junping Fang, Xinli Yu; Ulanqab Central Hospital, Dacheng 25 26 Wang, Dajun Liu, Xinhong Cao; Wencheng County People's Hospital, Yi Tian, 27 28 HaishengZhu,Wanchuan Liu; Wuhai People's Hospital, Zhaohai Zhou, Lei Shi; Wuhu Second People's 29 30 Hospital, Wuwang Fang, Manxin Chen; Wulate County People's 31 32 Hospital, ,FuqinHan,JianyeFu,Yunmei Wang; Wuqiang County People's Hospital, Binglu Liu, 33 34 YanliangZhang,Xiupin Yuan; Wuyishan Municipal Hospital, Qingfei Lin, Yun Chen; Xiangtan County 35 36 People's Hospital, Yuliang Zhu, ZhiqiangCai; Xing County People's Hospital, Xingping Li, LirongAo; 37 http://bmjopen.bmj.com/ 38 Xingshan County People's Hospital, Shubing Wu, Hui Zhang; Xinmi First People's Hospital, Fusheng 39 40 Zhao, Guangming Yang; Xinshao County People's Hospital, Renfei Liu, Wenwei Ai; Xiuwu County 41 42 People's Hospital, JianbaoChang,Haijie Zhao; Xuanhan County People's Hospital, Qijun Ran, Xuan Ma; 43 44 Xupu County People's Hospital, Shijun Jiang, Xiaochun Shu; Yanggao County People's Hospital, Zhiru 45 on September 25, 2021 by guest. Protected copyright. 46 Peng, Yan Han; Yanqing County Hospital, Jianbin Wang, Li Yang; Ying County People's Hospital, Yu 47 48 Shen, Xingcun Shang; Yitong Manchu Autonomous County First People's Hospital, Haifeng Wang; 49 50 Yongxing County People's Hospital, Hongyan Li, Zhisong Liao, Yang Cao; Yuanzhou District People's 51 52 Hospital of Guyuan City, Xiaoping Gao, MeiyingCai, Lining You; Yuncheng Central Hospital, Xuexin 53 54 Li, Shuqin Li, Yingjia Li; Yunlong County People's Hospital, Jianxun Yang, Song Ai, Jianfei Ma; 55 56 Yuyao People's Hospital, Lailin Deng; ZhangjiachuanHui Autonomous County First People's Hospital, 57 58 Keyu Wang, Shitang Gao, Jian Guan; Zhouning County Hospital, Banghua He, Youyi Lu; Zhuoni 59 60

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1 2 3 4 County People's Hospital, Weirong Yang, Hong Li; Zhuozi County People's Hospital, Zhizhong Zhang, BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 Xiaohong Chi; Zuoyun County People's Hospital, Ru Duan, Guangli Wang. 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 B. China PEACE hospital survey: design, conduction, and materials BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 Participants 7 8 In the collaborative network, we invited the principal investigator and the coordinator of each hospital 9 10 to participate in the survey. The definitions of the roles were established during the planning phase of 11 12 the China PEACE-Retrospective AMI Study: typically, the director of the Cardiology Department or 13 14 Internal Medicine Department at each hospital served as the principal investigator, and the China 15 16 PEACE study coordinator was most often a physician selected by the principal investigator. 17 18 Survey design For peer review only 19 20 We organized the survey in 4 sections: personal information of the respondent (part A); general 21 22 information about the hospital and the department in charge of AMI care (part B); information about 23 24 hospital practices relating to the diagnosis and treatment of cardiovascular heart disease (part C); and 25 26 organizational learning characteristics and quality improvement for AMI care (part D). Organizational 27 28 learning culture was measured using questions from the Short-Form Learning Organization Survey 29 30 (LOS-27) and the Survival after AMI (SAMI) study. 31 32 The survey was written in English and translated into Chinese. To ensure accuracy, a double translation 33 34 was conducted in which the survey was translated into Chinese and then back into English 35 36 independently by 2 bilingual Chinese medical researchers. Modifications were made to the Chinese 37 http://bmjopen.bmj.com/ 38 translation accordingly. Participants were informed at the start of the survey that their responses would 39 40 be used to study institutional characteristics and medical care patterns. 41 42 Survey conduction 43 44 The survey was piloted using a convenience sample of 6 hospitals with percutaneous coronary 45 on September 25, 2021 by guest. Protected copyright. 46 intervention capability. The principal investigators were invited to participate in the pilot, and one 47 48 study coordinator also volunteered to participate. The responses of the 6 principal investigators (3 via 49 50 in-person interviews and 3 via self-administered paper-based survey) and 1 study coordinator (via 51 52 self-administered paper-based survey) were collected. The cognitive interviewing methodology, in 53 54 which individual in-person interviews were conducted with each pilot participant, was used to assess 55 56 understanding of the pilot survey. For paper-based pilot surveys, cognitive interviewing consisted of 57 58 retrospective (post-survey) probes; for in-person interviews, concurrent (during survey) probes allowed 59 60

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1 2 3 4 Survey questionnaires BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 A. Personal information 6 7 A.1 Gender: 8 ○ Male ○ Female 9 A.2 Education 10 ○ Junior high school 11 ○ Senior high school (technical school or technical secondary school) 12 13 ○ College (junior college) 14 ○ Postgraduate 15 A.3 Clinical job title: 16 ○ Consultant ○ Attendant ○ Resident ○ Nurse ○ Other, please specify: ___ 17 18 A.4 Senior administrativeFor position peer in hospital: review only 19 ○ No ○ Yes, please specify: ___ 20 A.5 You have been working in the department for __ years. 21 22 23 B. General Information of the hospital and the department 24 25 Instructions: This section focuses on characteristics of your hospital and department. For all 26 questions, please reflect upon them during the 1-year period from 1/1/2011 to 12/31/2011 (for 27 some of them, please consider 1/1/2001 to 12/31/2001, and 1/1/2006 to 12/31/2006, as specified). 28 Even some questions in this section might be somewhat hard to answer immediately, especially 29 those about the characteristics of your hospital or department in 2001 and 2006. Please try best 30 to find the answer - as accurate as possible - to every applicable question. 31 32 B.1 Affiliated hospital of medical college: 33 ○ No ○ Yes, please specify the name of the college: ______[Skip to B3] 34 B.2 Teaching hospital of medical college: 35 ○ No ○ Yes, please specify the name of the college: ______36 37 Total No. in your department http://bmjopen.bmj.com/ 38 In 2001 In 2006 In 2011 39 40 B.3 Beds 41 B.4 Consultants 42 43 B.5 Attendants 44 45 B.6 Residents on September 25, 2021 by guest. Protected copyright. 46 B.7 Nurses 47 48 B.8 Is there any other department in your hospital providing inpatient treatment for AMI? 49 ○ No ○ Yes, please specify the name of the department: ______50 B.9 Coronary Care Unit (CCU) in hospital? 51 ○ No ○ Yes, please specify the No. of beds: ______52 53 B.10 Cath lab in hospital? 54 ○ No [Skip to B12] ○ Yes, please specify when started: ______55 B.11 How many qualified cardiac interventionalist there are in your hospital: ______○ 56 57 unknown 58 B.12 Could CABG be performed in hospital? 59 ○ No ○ Yes, please specify the No. of cases in 2011: ______60

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1 2 3 B.13 Independent emergency department? BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 4 ○ No ○ Yes, please specify the No. of cardiologists in charge in emergency department 5 normally: ______6 7 B.14 Formal GCP training of clinical staff in your department? 8 ○ No ○ Yes ○ Unknown 9 B.15 Have your apartment participated in international clinical trials? 10 11 ○ No ○ Yes, please specify the names of the trials: ______○ Unknown 12 B.16 SFDA certified site for CVD drug trials? 13 ○ No ○ Yes ○ Unknown 14 15 B.17 Existence of Ethics Committee in hospital? 16 ○ No ○ Yes ○ Unknown 17 Total No. in your hospital 18 For peer review only 19 In 2001 In 2006 In 2011 20 B.18 Patients with stroke 21 22 B.19 Patients with ischemic stroke 23 B.20 Patients with hemorrhagic stroke 24 25 B.21 Independent neurology department? 26 ○ No ○ Yes, please specify the No. of beds in the department: ______27 B.22 Carotid endarterectomy performed in hospital? 28 ○ No ○ Yes, please specify when started: ______○ Unknown 29 30 B.23 Carotid stenting performed in hospital? 31 ○ No ○ Yes, please specify when started: ______○ Unknown 32 The average cost of the following items in your hospital 33 34 Items Cost, ￥ 35 36 B.24 Biochemical test, including glucose, lipid, liver function, renal function, CRP or hsCRP http://bmjopen.bmj.com/ 37 B.25 Coagulation function test 38 39 B.26 BNP or NT-proBNP 40 B.27 41 Stress test 42 B.28 43 UCG 44 on September 25, 2021 by guest. Protected copyright. 45 B.29 46 Cardiac CT 47 B.30 48 Carotid US 49 50 51 C. Diagnosis and treatment for CHD 52 53 Instructions: This section focuses on hospital processes and care of patients with AMI. For all 54 questions, please reflect upon them during the 1-year period from 1/1/2011 to 12/31/2011. 55 C.1 56 Routine diagnostic test of CK for ACS patients after admission? 57 58 ○ No ○ Yes, please specify the average time delay in reporting results: ______○ Unknown 59 60

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1 2 3 C.2 4 Routine diagnostic test of CK-MB for ACS patients after admission? BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 ○ No ○ Yes, please specify the average time delay in reporting results: ______○ Unknown 7 C.3 8 Routine diagnostic test of troponin for ACS patients after admission? 9 10 ○ No ○ Yes, please specify the average time delay in reporting results: ______○ Unknown 11 12 C.4 13 Are patients who are stable after PCI admitted to an intensive care unit? SAMI-Q25 14 15 ○ Always ○ Usually ○ Sometimes ○ Rarely ○ Unknown 16 C.5 17 Did your emergency department use a uniform protocol to care for patients who arrived to the 18 For peer review only 19 emergency department with STEMI? SAMI-Q26 20 21 ○ No ○ Yes ○ Unknown 22 23 C.6 Did your emergency department use a uniform protocol to care for patients who arrived to the 24 25 emergency department with Unstable Angina/NSTEMI? SAMI-Q27 26 27 ○ No ○ Yes ○ Unknown 28 29 C.7 30 Did your hospital use simulations (i.e., trial exercises, dry-runs) to practice any of the following AMI 31 32 care processes? [Check all that apply] SAMI-Q28 33 34 □ Door-to-balloon or door-to-drug protocols 35 36 □ Chest pain in hospitalized patients 37 http://bmjopen.bmj.com/ 38 □ Inpatient codes (e.g., cardiac arrest, respiratory failure) 39 40 □ None above 41 42 □ Unknown 43 44 C.8

To which patient care unit were patients who were stable with Unstable Angina/NSTEMI most likely on September 25, 2021 by guest. Protected copyright. 45 46 admitted? SAMI-Q29 47 48 49 ○ CCU ○ ICU ○ Step-down unit ○ Designated chest pain/telemetry/cardiology floor 50 51 ○ General medicine floor ○ We did not have a routine method of assigning beds for patients with 52 53 Unstable Angina/NSTEMI ○ Unknown 54 C.9 55 Did all, or nearly all, patients with AMI have a cardiologist as their primary attending physician? 56 57 SAMI-Q30 58 59 ○ No ○ Yes [Skip to C11] ○ Unknown 60

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1 2 3 C.10 4 Were cardiology consults required for all patients with AMI? SAMI-Q30a BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 ○ No ○ Yes ○ Unknown 7 C.11 8 In the intensive care unit, who was primarily responsible for the care of patients with AMI? [Check 9 10 all that apply] SAMI-Q31 11 12 □ Critical care physicians (i.e., intensivists) 13 14 □ Cardiologist/s based exclusively in the unit 15 16 □ Other cardiologists 17 18 □ Other, pleaseFor specify: ______peer review only 19 20 □ Unknown 21 22 C.12 Electronic medical record? 23 ○ No [Skip to C14] ○ Yes, please specify when started: ______○ Unknown 24 C.13 25 Did your hospital use an electronic medical record (EMR) in the following areas? [Check all 26 27 that apply] SAMI-Q34 28 29 □ Emergency department 30 31 □ Inpatient floors 32 33 □ Critical care units 34 35 □ Affiliated ambulatory offices/clinics 36 37 http://bmjopen.bmj.com/ □ None above 38 39 C.14 40 On the inpatient floors, did your hospital have the following electronic capabilities? [Check all that 41 42 apply] SAMI-Q35 43 44 □ Computerized assisted physician order entry 45 on September 25, 2021 by guest. Protected copyright. 46 □ Computer prompts to alert user to potential drug-drug interactions or allergies 47 48 □ Computer prompts to alert user to potential errors in dosing and information 49 50 □ Computer prompts to alert user to medication order expiration 51 52 □ Computer prompts to improve adherence to core measures for AMI care (e.g., beta-blocker use) 53 54 □ None above 55 56 57 58 59 60

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1 2 3 C.15 4 In the emergency department, were prior ECG’s electronically available at the time of care? BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 SAMI-Q36 7 8 ○ No ○ Yes ○ Unknown 9 C.16 10 Did physicians regularly use explicit protocols or clinical pathways for patients with AMI? 11 12 SAMI-Q37 13 14 ○ No ○ Yes ○ Unknown 15 16 C.17 17 Did clinicians on the inpatient care units regularly use order sets (either paper-based or electronic) for 18 For peer review only 19 patients with STEMI? SAMI-Q38 20 21 ○ No ○ Yes ○ Unknown 22 C.18 23 Did clinicians on the inpatient care units regularly use order sets (either paper-based or electronic) for 24 25 with Unstable Angina/NSTEMI? SAMI-Q39 26 27 ○ No ○ Yes ○ Unknown 28 29 C.19 30 Which of the following types of physicians were at the hospital 24-hours/day and 7-days/week? 31 32 [Check all that apply] SAMI-Q42 33 34 □ Critical care physicians (i.e., intensivists) 35 36 □ Non-interventional cardiologists 37 http://bmjopen.bmj.com/ 38 □ Interventional cardiologists 39 40 □ Cardiology fellows (including non-interventional and interventional) 41 42 □ Hospitalists 43 44 □ None above 45 on September 25, 2021 by guest. Protected copyright. C.20 46 Are there any protocols used to guide nurses on when to call the attending cardiologist for patients 47 48 with AMI? SAMI-Q43 49 50 ○ No ○ Yes ○ Unknown 51 52 C.21 53 Patients with acute coronary syndrome who arrived by Emergency medical service (ambulance): 54 55 ○ None [Skip to C25] ○ 1–25% ○ 26–50% ○ 51–75% ○ 76-100% ○ 56 57 Unknown 58 59 60

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1 2 3 C.22 4 Emergency medical service routinely gives pre-alert calls? BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 ○ No ○ Yes ○ Unknown 7 C.23 8 Patients with acute coronary syndrome who undergo ECG en route to hospital: 9 10 ○ None ○ 1–25% ○ 26–50% ○ 51–75% ○ 76-100% ○ Unknown 11 12 C.24 13 Emergency medical service routinely tell your hospital the results of ECG? 14 15 ○ No ○ Yes ○ Unknown 16 C.25 17 Formal training of triage staff for assessing acute coronary syndrome? 18 For peer review only 19 ○ No ○ Yes ○ Unknown 20 21 C.26 Dedicated space in triage area for immediate ECG? 22 23 ○ No ○ Yes ○ Unknown 24 25 C.27 26 Written criteria for immediate ECG in emergency department? 27 28 ○ No ○ Yes ○ Unknown 29 C.28 30 Expected interval between patients’ arriving and ECG? 31 32 ○ ≤5 min ○ 6–20 min ○ >20 min ○ No expected time ○ Unknown 33 34 C.29 35 Dedicated ECG technicians in emergency department? 36 37 ○ No ○ Yes, only some shifts ○ Yes, always ○ Unknown http://bmjopen.bmj.com/ 38 39 C.30 Thrombolysis for AMI patients in hospital? 40 ○ No [Skip to C38] ○ Yes, please specify when started: _____ 41 42 C.31 43 Does your hospital have a set protocol to identify eligible patients for thrombolysis? 44

○ No ○ Yes ○ Unknown on September 25, 2021 by guest. Protected copyright. 45 C.32 46 Does your hospital have a set protocol to assess contraindications of thrombolysis? 47 48 ○ No ○ Yes ○ Unknown 49 50 C.33 51 Who makes the decision about thrombolysis in your hospital? 52 53 ○ Emergency medicine physician alone 54 55 ○ Emergency medicine physician with a cardiac consultation 56 57 ○ Only Cardiologist 58 59 ○ Unknown 60

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1 2 3 C.34 4 In your hospital, where do patients with AMI receive thrombolysis? BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 ○ In the emergency department 7 8 ○ In the cardiology department (or general medicine department) 9 10 ○ In the ICU or CCU 11 12 ○ Unknown 13 C.35 14 Where are the thrombolytic medicines stored and prepared? 15 16 ○ Stored and prepared in the department where thrombolysis is done 17 18 ○ PreparedFor in the department peer where review thrombolysis is done, only but stored in another location 19 20 ○ Stored and prepared in some location other than the department where thrombolysis is done 21 22 ○ Unknown 23 24 C.36 25 Informed Consent before thrombolysis? 26 27 ○ Not necessary 28 29 ○ Only orally obtained informed consent is needed 30 31 ○ One written informed consent form is needed 32 33 ○ More than one written informed consent form is needed 34 35 ○ Unknown 36 C.37 http://bmjopen.bmj.com/ 37 Prepayment before thrombolysis? 38 39 ○ No 40 41 ○ Yes, please specify the average amount approximately: ___ (“-1” if unknown) 42 43 ○ Unknown 44 on September 25, 2021 by guest. Protected copyright. 45 C.38 46 Primary PCI was performed in your hospital for STEMI patients? 47 48 ○ No [Skip to C60] ○ Yes, please specify when started: ___ 49 C.39 50 Activation of catheterization laboratory on weekdays? 51 52 ○ Emergency medicine physician with cardiologist 53 54 ○ Cardiologist alone 55 56 ○ Emergency medicine physician alone 57 58 ○ Unknown 59 60

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1 2 3 C.40 4 Activation of catheterization laboratory at night and on weekends? BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 ○ Emergency medicine physician with cardiologist 7 8 ○ Cardiologist alone 9 10 ○ Emergency medicine physician alone 11 12 ○ Unknown 13 C.41 14 Process for activating catheterization team? 15 16 ○ After communicating with the emergency department, interventional cardiologist activates 17 18 catheterizationFor laboratory peer by calling review staff or a central page only operator 19 20 ○ Emergency department makes at least two calls: one to the interventional cardiologist and 21 22 another to a central page operator, who pages catheterization laboratory staff 23 24 ○ Emergency department makes a single call to a central page operator, who then pages 25 26 interventional cardiologist and catheterization laboratory staff 27 28 ○ No standard approach 29 30 ○ Other 31 32 ○ Unknown 33 34 C.42 35 Activation of on-call staff for catheterization laboratory? 36 37 ○ Page operator is not used http://bmjopen.bmj.com/ 38 39 ○ Page operator is used; confirmation of page receipt is required 40 41 ○ Page operator is used; no confirmation of page receipt is required 42 43 ○ No standard approach 44 45 ○ Unknown on September 25, 2021 by guest. Protected copyright. 46 47 C.43 First physician notified after STEMI diagnosis in emergency department? 48 49 ○ Cardiologist ○ Interventional cardiologist ○ Patient’s primary care physician 50 51 ○ Other or variable ○ Unknown 52 53 C.44 54 Laboratory and radiographic results are needed to activate catheterization laboratory? 55 56 ○ Yes ○ No ○ No standard approach ○ Unknown 57 58 59 60

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1 2 3 C.45 4 Process after emergency medical service transmits ECG results? BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 ○ Emergency department waits for patient to arrive at hospital to determine whether 7 8 catheterization laboratory should be activated 9 10 ○ Emergency department contacts cardiologist while the patient is en route to determine whether 11 12 catheterization laboratory should be activated 13 14 ○ Emergency department activates catheterization laboratory while the patient is still en route to 15 16 the hospital 17 18 ○ No standardFor approach peer or variable reviewapproach only 19 20 ○ Not applicable because ECG data not transmitted en route 21 22 ○ Not applicable because ECG never performed en route 23 24 ○ Unknown 25 26 C.46 Expected interval between page and arrival of staff in catheterization laboratory? 27 28 ○ ≤20 min ○ 21–30 min ○ >30 min ○ No expected time ○ Unknown 29 30 C.47 31 Expected interval between page and arrival of interventional cardiologist? 32 33 ○ ≤20 min ○ 21–30 min ○ >30 min ○ No expected time ○ Unknown 34 C.48 35 Someone is always available to transport patients from emergency department to catheterization 36 http://bmjopen.bmj.com/ 37 laboratory? 38 39 ○ No ○ Yes ○ Unknown 40 41 C.49 42 Initiation of patient transport from emergency department to catheterization laboratory? 43 44 ○ After catheterization laboratory notifies emergency department it is ready 45 on September 25, 2021 by guest. Protected copyright. 46 ○ A set interval after the decision is made regarding PCI 47 48 ○ No standard approach 49 50 ○ Other approach 51 52 ○ Unknown 53 54 55 56 57 58 59 60

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1 2 3 C.50 4 Minimum number of nurses and technicians required in catheterization laboratory before patient BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 is transported from emergency department? 7 8 ○ Interventional cardiologist must be present 9 10 ○ Interventional cardiologist may not be present but need presence of 1 staff person 11 12 ○ Interventional cardiologist may not be present but need presence of 2-4 staff person 13 14 ○ No set number 15 16 ○ Unknown 17 C.51 18 Elective catheterizationFor peer cases rescheduled review for emergency only PCI? 19 20 ○ Yes ○ No ○ It depends ○ Unknown 21 22 C.52 23 If interventionalist is present, number of staff required to begin PCI? 24 25 ○ 1 ○ 2 ○ 3 ○ 4 ○ Unknown 26 C.53 27 Catheterization laboratory is left so that next PCI can begin promptly? 28 29 ○ Yes ○ No ○ No standard policy ○ Unknown 30 31 C.54 32 Cardiology fellows participate in performing PCI? 33 34 ○ No ○ Yes ○ Unknown 35 C.55 36 Staff in critical care area are routinely cross-trained to cover catheterization laboratory? 37 http://bmjopen.bmj.com/ 38 ○ No ○ Yes ○ Unknown 39 40 C.56 Location of catheterization laboratory? 41 42 ○ Elevator required to travel from emergency department 43 44

○ Same floor as emergency department on September 25, 2021 by guest. Protected copyright. 45 46 C.57 47 An attending cardiologist is always at the hospital? 48 49 ○ No ○ Yes ○ Unknown 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 C.58 4 Informed Consent before primary PCI? BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 ○ Not necessary 7 8 ○ Only orally obtained informed consent is needed 9 10 ○ One written informed consent form is needed 11 12 ○ More than one written informed consent form is needed 13 14 ○ Unknown 15 C.59 16 Prepayment before primary PCI? 17 18 ○ No For peer review only 19 20 ○ Yes, please specify the average amount approximately ___ (“-1” if unknown) 21 22 ○ Unknown 23 24 C.60 25 Does your hospital measure the following time intervals? [Check all that apply] 26 27 □ Door to ECG 28 29 □ Door to needle 30 31 □ Door to balloon 32 33 □ None above 34 35 □ Unknown 36 C.61 http://bmjopen.bmj.com/ 37 Do your hospital feedback the time intervals to someone? [Check all that apply] 38 39 □ No 40 41 □ Yes, to physician staff involved in the care 42 43 □ Yes, to nursing staff involved in the care 44 45 on September 25, 2021 by guest. Protected copyright. □ Yes, to pharmacy staff involved in the care 46 47 □ Yes, to other staff involved in the care 48 49 □ Unknown 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 C.62 4 Do your hospital report the analyze results about the time intervals regularly? [Check all that apply] BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 □ No 7 8 □ Yes, to departments involved in the care (the emergency department, the cardiology department) 9 10 □ Yes, to other department in your hospital 11 12 □ Yes, to other institutions outside your hospital 13 14 □ Unknown 15 16 17 D. Organizational learning characteristics 18 For peer review only 19 Instructions: This section focuses on the organizational learning and measurements to improve 20 AMI care, including supportive environment and leadership, experimentation and training, 21 knowledge acquisition, reflection and performance monitoring, etc. Please draw on your own 22 experiences in your current role working with clinical staff and administration. For all 23 questions, please reflect upon them during the 1-year period from 1/1/2011 to 12/31/2011. 24 Although some questions in this section look similar, there are differences between them and 25 you should treat each one as a separate question. The best approach is to answer each question 26 fairly quickly. That is, don’t try to count up the number of times you felt a particular way, but 27 rather indicate the alternative that seems most reasonable. 28 29 The definition of “workgroup” below is the department, unit, ward, or group caring AMI 30 patients that you are working at. 31 This section adopts 7-point (from highly inaccurate to highly accurate). If you think the options 32 are difficult to understand or distinguish, please grade the accuracy here using actual numbers, 33 while 1 is the lowest (highly inaccurate), 7 is the highest (highly accurate), then choose the 34 corresponding option. 35 D.1 36 In this workgroup, people value new ideas. 37 http://bmjopen.bmj.com/ 38 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 39 40 ○ highly accurate 41 42 D.2 43 Clinicians are encouraged to creatively solve problems related to AMI care processes. (60) 44 45 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always on September 25, 2021 by guest. Protected copyright. 46 D.3 47 Innovative ideas about AMI care are shared widely in the hospital. (61) 48 49 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 50 51 D.4 Differences in opinions are welcomed in this workgroup. 52 53 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 54 55 ○ highly accurate 56 57 58 59 60

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1 2 3 D.5 4 In this workgroup, people are open to alternative ways of getting work done. BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 7 8 ○ highly accurate 9 D.6 10 People in this workgroup are eager to share information about what doesn’t work as well as to share 11 12 information about what does work. 13 14 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 15 16 ○ highly accurate 17 18 D.7 For peer review only 19 This workgroup frequently compares its performance to: Best-in-class organizations. 20 21 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 22 23 ○ highly accurate 24 D.8 25 This workgroup frequently compares its performance to: Other similar workgroups. 26 27 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 28 29 ○ highly accurate 30 31 D.9 32 This workgroup consistently collects information on technological trends. 33 34 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 35 36 ○ highly accurate 37 http://bmjopen.bmj.com/ D.10 38 If you make a mistake in this workgroup, it is often held against you. (Among clinicians taking care 39 40 of patients with AMI, there is a tendency to blame individuals for errors in patient care). (66) 41 42 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 43 44 D.11

Clinicians caring for patients with AMI are easily able to address problems and tough issues with on September 25, 2021 by guest. Protected copyright. 45 46 their department heads/chiefs. (56) 47 48 49 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 50 D.12 51 Department heads/chiefs are easily able to address problems and tough issues with senior level 52 53 administration.(57) 54 55 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 56 57 D.13 Nurses are comfortable checking with physicians if they have concerns about patient care.(65) 58 59 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 60

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1 2 3 D.14 4 Clinicians involved in the care of patients with AMI value each others’ skills and talents (e.g., BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 physicians value nurses’ skills and talents and vice-versa).(58) 7 8 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 9 D.15 10 Clinicians involved in the care of patients with AMI avoid sharing responsibility for medical errors. 11 12 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always. (59) 13 14 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 15 16 D.16 17 Were physicians explicitly encouraged to disclose medical errors to patients or their family 18 For peer review only 19 members? (7) 20 21 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 22 D.17 23 This workgroup engages in productive conflict and debate during discussions. 24 25 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 26 27 ○ highly accurate 28 29 D.18 30 In this workgroup, we frequently identify and discuss underlying assumptions that might affect key 31 32 decisions. 33 34 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 35 36 ○ highly accurate 37 http://bmjopen.bmj.com/ D.19 38 The hospital has the resources and information it needs to reduce 30-day mortality rates in patients 39 40 with AMI. (51) 41 42 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 43 44 D.20

Senior-level administration is supportive of efforts to improve AMI care. (52) on September 25, 2021 by guest. Protected copyright. 45 46 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 47 48 D.21 49 There is simply no time for reflection in this workgroup. 50 51 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 52 53 ○ highly accurate 54 D.22 55 In this workgroup, people are too busy to invest time in improvement. 56 57 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 58 59 ○ highly accurate 60

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1 2 3 D.23 4 My manager(s) establish(es) forums for and provide(s) time and resources for identifying problems BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 and organizational challenges. 7 8 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 9 10 ○ highly accurate 11 D.24 12 My manager(s) establish(es) forums for and provide(s) time and resources for reflecting and 13 14 improving on past performance. 15 16 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 17 18 ○ highly accurateFor peer review only 19 20 D.25 21 My manager(s) listen(s) attentively. 22 23 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 24 25 ○ highly accurate 26 D.26 27 My manager(s) invite(s) input from others in discussions. 28 29 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 30 31 ○ highly accurate 32 33 D.27 34 This workgroup experiments frequently with new product/service offerings. 35 36 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 37 http://bmjopen.bmj.com/ 38 ○ highly accurate 39 D.28 40 This workgroup experiments frequently with new ways of working. 41 42 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 43 44 ○ highly accurate 45 on September 25, 2021 by guest. Protected copyright. 46 D.29 This workgroup frequently employs pilot projects or simulations when trying our new ideas. 47 48 49 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 50 51 ○ highly accurate 52 D.30 53 This workgroup has a formal process for conducting and evaluating experiments or new ideas. 54 55 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 56 57 ○ highly accurate 58 59 60

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1 2 3 D.31 4 Experienced employees in this workgroup receive training when new initiatives are launched. BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 7 8 ○ highly accurate 9 D.32 10 Experienced employees in this workgroup receive training when shifting to a new position. 11 12 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 13 14 ○ highly accurate 15 16 D.33 17 Newly hired employees in this workgroup receive adequate training. 18 For peer review only 19 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 20 21 ○ highly accurate 22 D.34 23 Did your hospital provide training to EMS providers about AMI care? (17) 24 25 ○ Yes, about monthly 26 27 ○ Yes, about quarterly 28 29 ○ Yes, about annually 30 31 ○ Yes, other: ______32 33 ○ No 34 35 ○ Unknown 36 http://bmjopen.bmj.com/ 37 D.35 38 This workgroup has forums for meeting with and learning from: Experts from outside the 39 40 organization. 41 42 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 43 44 ○ highly accurate 45 on September 25, 2021 by guest. Protected copyright. D.36 46 This workgroup has forums for meeting with and learning from: Experts from other 47 48 departments/teams/divisions. 49 50 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 51 52 ○ highly accurate 53 54 D.37 55 This workgroup has forums for meeting with and learning from: Customers/clients. 56 57 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 58 59 ○ highly accurate 60

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1 2 3 D.38 4 This workgroup regularly conducts post-audits, after-action reviews, and debriefings. BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 ○ highly inaccurate ○ inaccurate ○ somewhat inaccurate ○ not sure ○ somewhat accurate ○ accurate 7 8 ○ highly accurate 9 D.39 10 Did your hospital have regular ‘morbidity and mortality’ conferences (or another educational 11 12 session) for discussing individual cases involving patients with AMI? (5) 13 14 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 15 16 D.40 17 Did your hospital review the deaths of patients with AMI? (4a) 18 For peer review only 19 ○ No, we did not review these cases (go to D44) 20 21 ○ Yes, we reviewed only deaths with potential quality issues (i.e., unexpected deaths) 22 23 ○ Yes, we reviewed all deaths 24 25 ○ Other, please specify: ______26 27 ○ Unknown 28 D.41 29 Did your hospital have a designated person or group to review the deaths of patients with AMI 30 31 (i.e., on an individual case level) that occurred during hospitalization? (4) 32 33 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 34 35 D.42 36 How long after the occurrence of the death were the cases typically reviewed? (4b) 37 http://bmjopen.bmj.com/ 38 ○ Within one week of the death 39 40 ○ Within one month of the death 41 42 ○ Within 3 months of the death 43 44 ○ Other, please specify: ______45 on September 25, 2021 by guest. Protected copyright. 46 ○ We did not have a set timeframe for reviewing these cases 47 48 ○ Unknown 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 D.43 4 Who usually reviewed these cases? (4c) BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 a. Senior management of the hospital 7 8 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 9 10 b. Cardiology chiefs 11 12 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 13 14 c. Nursing directors 15 16 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 17 18 d. Other physiciansFor participatingpeer in reviewthe care of patients withonly AMI 19 20 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 21 22 e. Quality Improvement/Quality Management department staff 23 24 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 25 26 D.44 Did your hospital have a designated person or group to review any of the following adverse events 27 28 in patients with AMI (i.e., on an individual case level)? (6) 29 30 a. Sentinel events (unexpected occurrence involving death or serious physical or psychological 31 32 injury) that occurred during hospitalization 33 34 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 35 36

D.45 on September 25, 2021 by guest. Protected copyright. 45 How long after the occurrence of these adverse events were the cases typically reviewed? (6a) 46 47 ○ Within one week of the adverse event 48 49 ○ Within one month of the adverse event 50 51 ○ Within 3 months of the adverse event 52 53 ○ Other, please specify: ______54 55 ○ We did not have a set timeframe for reviewing these cases 56 57 ○ Unknown 58 59 60

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1 2 3 D.46 4 Who usually reviewed these cases? (6b) BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 a. Senior management of the hospital 7 8 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 9 10 b. Cardiology chiefs 11 12 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 13 14 c. Nursing directors 15 16 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 17 18 d. Other physiciansFor participating peer in the carereview of patients with AMIonly 19 20 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 21 22 e. Quality Improvement/Quality Management department staff 23 24 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 25 26 f. Other, please specify: ___ 27 28 D.47 Did your hospital use root cause analysis or a similar method to understand the following problems 29 30 in AMI care? 31 32 a. Poor adherence to the core medication (i.e., anti-platelet agents) measures 33 34 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 35 36

b. Delay to fibrinolytic therapy or percutaneous coronary intervention (PCI) http://bmjopen.bmj.com/ 37 38 39 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 40 D.48 41 Did your hospital review data on 30-day mortality rates (deaths occurring within 30 days of 42 43 admission, including both inpatient and post-discharge deaths) in patients admitted with AMI (Check 44 45 all that apply) (10) on September 25, 2021 by guest. Protected copyright. 46 47 □ Yes, through the medical insurance data system 48 49 □ Yes, through a regional database system 50 51 □ Yes, we internally collect our own data on deaths 52 53 □ Yes, other, please specify: ___ 54 55 □ No [Skip to D52] 56 57 □ Unknown 58 59 60

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1 2 3 D.49 4 How quickly were mortality rates in patients with AMI available to your hospital (i.e., what BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 was the most current data available to your hospital)? (10a) 7 8 ○ Within 6 months of care delivery 9 10 ○ 6 months to 1 year after care delivery 11 12 ○ 1 - 2 years after care delivery 13 14 ○ Less frequently than 2 years of care delivery 15 16 ○ Unknown 17 D.50 18 Did your Forhospital regularly peer compare review its performance toonly other hospitals on either inpatient in 19 20 patients with AMI? (14) 21 22 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 23 24 D.51 25 Did your hospital have efforts to improve any of the following inpatient acute myocardial infarction 26 27 (AMI) quality measures? (1) 28 29 a. Adherence to the core medication (i.e., anti-platelet agents) measures 30 31 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 32 33 b. Time to fibrinolytic therapy or percutaneous coronary intervention (PCI) 34 35 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 36 D.52 http://bmjopen.bmj.com/ 37 Beyond these quality measures, did your hospital initiate efforts to improve any of the following in 38 39 patients admitted with AMI? (2) 40 41 a. Inpatient mortality in patients with AMI 42 43 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 44 45 on September 25, 2021 by guest. Protected copyright. b. Post-discharge mortality (death occurring after discharge, but within 30 days of admission) in 46 47 patients with AMI 48 49 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 50 51 c. Readmission within 30 days from prior admission in patients with AMI 52 53 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 54 55 56 57 58 59 60

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1 2 3 D.53 4 Did your hospital have a quality improvement team(s) devoted to improving: (3) BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 a. Inpatient mortality in patients with AMI 7 8 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 9 10 b. Post-discharge mortality (death occurring after discharge, but within 30 days of admission) in 11 12 patients with AMI 13 14 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 15 D.54 16 3a. Please indicate members of either the inpatient or post-discharge mortality team(s). 17 18 a. Senior managementFor of peerthe hospital review only 19 20 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 21 22 b. Hospital governing board 23 24 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 25 26 c. Chief of cardiology 27 28 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 29 30 d. Nursing directors 31 32 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 33 34 e. Other physicians participating in the care of patients with AMI 35 36

D.55 on September 25, 2021 by guest. Protected copyright. 45 Nurses are engaged in efforts to improve AMI care. (53) 46 47 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 48 49 D.56 Cardiologists are engaged in efforts to improve AMI care. (54) 50 51 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 52 53 D.57 54 Emergency medicine physicians are engaged in efforts to improve AMI care. (55) 55 56 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 57 58 59 60

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1 2 3 D.58 4 Did your hospital have one or more physician champions focused on improving either inpatient or BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 30-day mortality in patients with AMI? (12) 7 8 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 9 D.59 10 Did your hospital have one or more nurse champions focused on improving either inpatient or 11 12 30-day mortality in patients with AMI? (13) 13 14 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 15 16 D.60 17 After we make changes to improve AMI care, we fail to evaluate their effectiveness. (67) 18 For peer review only 19 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 20 D.61 21 Did cardiology and emergency department staff meet together to review care for patients with AMI? 22 23 (15) 24 25 ○ Yes, about monthly 26 27 ○ Yes, about quarterly 28 29 ○ Yes, about annually 30 31 ○ Yes, other: ______32 33 ○ No [Skip to D63] 34 35 ○ Unknown 36 http://bmjopen.bmj.com/ 37 D.62 38 What was typically discussed at these meetings? (15a). 39 40 a. Care of patients with ST-elevation myocardial infarction (STEMI) 41 42 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 43 44 b. Care of patients with Unstable Angina/non-STEMI (NSTEMI) 45 on September 25, 2021 by guest. Protected copyright. 46 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 47 48 c. Care of patients with chest pain, in general 49 50 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 51 52 53 54 55 56 57 58 59 60

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1 2 3 D.63 4 Did clinicians from your hospital meet with emergency medical system (EMS) providers to review BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 the care of patients with AMI? (16) 7 8 ○ Yes, about monthly 9 10 ○ Yes, about quarterly 11 12 ○ Yes, about annually 13 14 ○ Yes, other: ______15 16 ○ No 17 18 ○ Unknown For peer review only 19 D.64 20 There is good coordination among the different departments involved with the care of patients with 21 22 AMI. (62) 23 24 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 25 26 D.65 27 Departments caring for patients with AMI (e.g., cardiology, emergency medicine) communicate 28 29 easily with each other.(64) 30 31 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 32 D.66 33 Clinicians caring for patients with AMI share new evidence-based approaches with the AMI 34 35 team.(63) 36 http://bmjopen.bmj.com/ 37 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 38 39 D.67 40 Which best describes the quality of your interaction with hospitals that referred patients to you 41 42 with AMI?(18) 43 44 ○ Very collaborative (we shared data along with strategies for improving AMI care) ○ Somewhat 45 on September 25, 2021 by guest. Protected copyright. 46 collaborative (we communicated regularly, but we did not share data and strategies) 47 48 ○ Not collaborative (we had no or minimal contact with the referring hospital/s) 49 50 ○ Not applicable [Skip to D69] 51 52 53 54 55 56 57 58 59 60

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1 2 3 D.68 4 Did your hospital routinely give feedback to the referring hospital/s on any of the following? BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 (18a.) 7 8 a. Time to transfer 9 10 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 11 12 b. AMI-related procedures performed 13 14 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always 15 16 c. Patient outcome 17 18 ○ NeverFor ○ Rarely peer○ Sometimes ○review Usually ○ Always only 19 20 d. Other please specify: ______21 D.69 22 Which best describes the quality of your interaction with hospitals that you referred patients to 23 24 with AMI? (19) 25 26 ○ Very collaborative (we shared data along with strategies for improving AMI care) ○ Somewhat 27 28 collaborative (we communicated regularly, but we did not share data and strategies) 29 30 ○ Not collaborative (we had no or minimal contact with hospitals in our region) 31 32 ○ Not applicable 33 34 D.70 35 Was your hospital part of a regional effort or consortium of hospitals to improve AMI care? (20) 36 37 ○ Never ○ Rarely ○ Sometimes ○ Usually ○ Always http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 C. Definition of In-hospital Complications BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 1) Re-infarction 7 8 Indicate if there is physician documentation of recurrent myocardial infarction during hospitalization. 9 10 11 12 2) Cardiogenic shock 13 14 Indicate if there is physician documentation of cardiogenic shock during hospitalization. 15 16 17 18 3) Ischemic strokeFor peer review only 19 20 Indicate if there are physician documentations of new-onset ischemia stroke and stroke-related 21 22 symptoms during hospitalization. The stroke-related symptoms include: trouble walking/loss of 23 24 balance/incoordination, one-sided numbness or hemi-anesthesia, one-sided facial numbness or 25 26 hemi-anesthesia, mouth askew and drooling, dysarthria or slurred speech, loss of vision or blurred 27 28 version in one or both eyes, dizziness with vomiting, severe headache and vomiting, unconsciousness, 29 30 and hyperspasmia. 31 32 33 34 4) Congestive heart failure 35 36 Indicate if there is physician documentation of heart failure during hospital stay. This include those 37 http://bmjopen.bmj.com/ 38 without a history of heart failure but develop heart failure during hospitalization, and those with a 39 40 history of heart failure as a chronic comorbidity and develop worsening heart failure during 41 42 hospitalization. 43 44 45 on September 25, 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 D. Baseline characteristics of patients with hypokalaemia BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 Characteristics Overall Use N(%) Non-Use(%) P value 7 8 Patient characteristics 9 10 Age 0.005 11 12 <55 753(19.9) 170(20) 583(19.8) 13 55-64 873(23) 225(26.5) 648(22) 14 15 65-74 1135(29.9) 260(30.6) 875(29.8) 16 17 >=75 1029(27.2) 195(22.9) 834(28.4) 18 For peer review only 19 Gender 0.621 20 21 Female 1508(39.8) 332(39.1) 1176(40) 22 Male 2282(60.2) 518(60.9) 1764(60) 23 24 Hypertension 2318(61.2) 547(64.4) 1771(60.2) 0.060 25 26 Diabetes 655(17.3) 131(15.4) 524(17.8) 0.101 27 28 Dyslipidemia 212(5.6) 38(4.5) 174(5.9) 0.106 29 Currently smoking 1170(30.9) 286(33.6) 884(30.1) 0.057 30 31 Prior ischemic stroke 452(11.9) 102(12) 350(11.9) 0.940 32 33 Prior myocardial infarction 325(8.6) 91(10.7) 234(8) 0.012 34 35 Prior CABG/PCI 97(2.6) 23(2.7) 74(2.5) 0.759 36

Chest discomfort 3380(89.2) 764(89.9) 2616(89) 0.455 http://bmjopen.bmj.com/ 37 38 Left branch block at 39 59(1.6) 16(1.9) 43(1.5) 0.384 40 presentation 41 42 Cardiac arrest at presentation 80(2.1) 28(3.3) 52(1.8) 0.006 43 Cardiogenic shock at 44

306(8.1) 83(9.8) 223(7.6) 0.040 on September 25, 2021 by guest. Protected copyright. 45 presentation 46 47 Acute stroke at presentation 102(2.7) 16(1.9) 86(2.9) 0.098 48 49 Heart rate at presentation, bpm 0.457 50 51 <50 163(4.3) 36(4.2) 127(4.3) 52 50-110 3331(87.9) 739(86.9) 2592(88.2) 53 54 >110 296(7.8) 75(8.8) 221(7.5) 55 56 SBP at presentation, mmHg 0.046 57 58 <120 1263(33.3) 314(36.9) 949(32.3) 59 120-139 1096(28.9) 223(26.2) 873(29.7) 60

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1 2 3 4 140-159 771(20.3) 162(19.1) 609(20.7) BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 >=160 660(17.4) 151(17.8) 509(17.3) 6 7 Reperfusion therapies <0.001 8 9 No reperfusion 557(14.7) 156(18.4) 401(13.6) 10 11 Fibrinolytic therapy 2809(74.1) 585(68.8) 2224(75.6) 12 Primary PCI 424(11.2) 109(12.8) 315(10.7) 13 14 Hospital characteristics 15 16 Teaching hospital 3042(80.3) 707(83.2) 2335(79.4) 0.015 17 18 PCI capable hospitalFor peer2455(64.8) review 581(68.4) only1874(63.7) 0.013 19 Hospital level 0.047 20 21 Secondary or lower 1507(39.8) 313(36.8) 1194(40.6) 22 23 Tertiary hospital 2283(60.2) 537(63.2) 1746(59.4) 24 25 Economic geographic region 0.682 26 Eastern 798(21.1) 184(21.6) 614(20.9) 27 28 Central 2163(57.1) 474(55.8) 1689(57.4) 29 30 Western 829(21.9) 192(22.6) 637(21.7) 31 32 Urban/Rural 0.023 33 Rural 1739(45.9) 361(42.5) 1378(46.9) 34 35 Urban 2051(54.1) 489(57.5) 1562(53.1) 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

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1 2 3 4 E. Predictors of the use of IV magnesium sulphate BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5

6 7 Unadjusted Adjusted 8 9 Variable OR (95%CI) P value OR (95%CI) P value 10 11 New onset of heart failure 1.86(1.51-2.28) <0.0001 1.69(1.37-2.09) <0.0001 12 13 Cardiac arrest at 14 15 presentation 3.81(2.5-5.82) <0.0001 3.38(2.19-5.21) <0.0001 16 Aspirin within 24-hour 1.7(1.51-1.93) <0.0001 1.43(1.22-1.67) <0.0001 17 18 Statins within 24For-hour peer1.64(1.45 review-1.85) <0.0001 only 1.33(1.13-1.57) 0.0005 19 20 Reperfusion therapies 21 22 None - - 23 Fibrinolytic therapy 1.57(1.33-1.85) <0.0001 1.6(1.35-1.9) <0.0001 24 25 Primary PCI 1.65(1.42-1.92) <0.0001 1.69(1.44-1.98) <0.0001 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

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1 2 3 4 F. Correlations between positive response rate of LOS-27 and IV magnesium sulphate BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 use 7 8 100% 9 10 80% 11 60% 12 13 40% 14 20% 15 16 0% 17 0% 20% 40% 60% 80% 100% 18 -20% For peer review only 19 -40% 20 -60%

21 IV magnesium sulfate use reduction from 2011 to 2015 reduction from 2011 22 -80% 23 24 -100% Positive response rate of LOS-27 25 26 27 28 29 100% 30 90% 31 32 80% 33 70% 34 35 60% 36 50% 37 http://bmjopen.bmj.com/ 40% 38 39 30% 40 20% 41 Risk-standardized rate of IV 10% 42 magnesium sulfate use in 2015 43 0% 44 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 45 Positive response rate of LOS-27 on September 25, 2021 by guest. Protected copyright. 46 47 48

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1 2 3 4 G. Comparisons between patients with and without IV magnesium sulfate therapy after BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 propensity score matching 7 Characteristics Use N(%) Non-Use(%) P value 8 9 Patient characteristics 10 11 Age 1072(24.4) 1037(23.6) .794 12 55-64 13 1290(29.4) 1283(29.2) 65-74 14 938(21.3) 959(21.8) 15 <55 1094(24.9) 1115(25.4) 16 >=75 17 18 Gender For peer review only 1346(30.6) 1299(29.6) .274 19 Female 20 3048(69.4) 3095(70.4) Male 21 2247(51.1) 2196(50) .277 22 Hypertension 889(20.2) 878(20) .77 23 Diabetes 24 235(5.3) 244(5.6) .672 25 Dyslipidemia 1496(34) 1470(33.5) .558 26 Currently smoking 27 28 Number of risk factors 2055(46.8) 1997(45.4) .445 29 1 30 1049(23.9) 1047(23.8) 2 31 232(5.3) 229(5.2) 32 >=3 1058(24.1) 1121(25.5) 33 None 34 Prior ischemic stroke 546(12.4) 484(11) .040 35 416(9.5) 382(8.7) .207 36 Prior myocardial infarction http://bmjopen.bmj.com/ 37 Prior CABG/PCI 104(2.4) 107(2.4) .834 38 4021(91.5) 4046(92.1) .331 39 Chest discomfort 40 Left branch block at presentation 65(1.5) 44(1.0) .043 41 81(1.8) 79(1.8) .873 42 Cardiac arrest at presentation 43 Cardiogenic shock at presentation 279(6.3) 236(5.4) .051 44 77(1.8) 66(1.5) .354 45 Acute stroke at presentation on September 25, 2021 by guest. Protected copyright. .733 46 Heart rate at presentation, bpm 47 177(4.0) 183(4.2) <50 48 3886(88.4) 3898(88.7) 49 50-110 331(7.5) 313(7.1) 50 >110 51 .621 52 SBP at presentation, mmHg 1565(35.6) 1607(36.6) 53 <120 54 1299(29.6) 1307(29.7) 120-139 55 913(20.8) 899(20.5) 56 140-159 617(14) 581(13.2) 57 >=160 58 59 Medication within 24 hours 60 Aspirin 2688(61.2) 2686(61.1) .965

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1 2 3 4 Statins 2398(54.6) 2442(55.6) .345 BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 ACE inhibitors or angiotensin receptor 2541(57.8) 2567(58.4) .574 6 Beta-blockers 1768(40.2) 1748(39.8) 7 blockers 0 8 Clopidogrel 1845(42) 1894(43.1) .290 9 .941 Reperfusion therapies 10 3130(71.2) 3131(71.3) 11 No reperfusion 746(17.0) 754(17.2) 12 Fibrinolytic therapy 13 518(11.8) 509(11.6) 14 Primary PCI

15 Hospital characteristics 16 3462(78.8) 3530(80.3) .072 Teaching hospital 17 2768(63.0) 2788(63.5) .650 18 PCI-capable hospitalFor peer review only .451 19 Hospital level 20 1576(35.9) 1610(36.6) 21 Secondary or lower 2818(64.1) 2784(63.4) 22 Tertiary 23 24 Economic geographic region 1115(25.4) 1186(27.0) .191 25 Central 26 2360(53.7) 2288(52.1) Eastern 27 919(20.9) 920(20.9) 28 Western

29 Urban/Rural 30 1724(39.2) 1721(39.2) .948 31 Rural 2670(60.8) 2673(60.8) 32 Urban 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 H. Trends different dosage of intravenous magnesium sulfate therapy in 2001, 2006, BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 6 2011 and 2015 in five economic-geographic regions. 7 8 9 10 Single dosage of intravenous magnesium sulfate therapy 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 Multiple dosage of intravenous magnesium sulfate therapy 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 I. Different dosage of IV magnesium sulfate use in 2001, 2006, 2011 and 2015 among BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 all hospitals. 6 7 8 Single dose of IV magnesium sulfate 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Multiple doses of IV magnesium sulfate 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 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 J. In-hospital outcomes between patients with different dosage of and without IV BMJ Open: first published as 10.1136/bmjopen-2019-033269 on 26 March 2020. Downloaded from 5 magnesium sulphate. 6 7 8 Single dose compared with no-use of IV magnesium sulphate 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 Multiple doses compared with no-use of IV magnesium sulphate 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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