Study design
The GAMI project is a multi-center, prospective, cluster-randomized intervention study with regional intervention conducted in 8 regions which represented different economic and medical resource levels in south China since 2016. The objective of the study was to evaluate the effectiveness of regional interventions, including enhanced public education and regional network construction, on the change of treatment delay of the STEMI patient’s treatment. Consecutive STEMI patients were enrolled from the major PCI centers of the regions. By analyzing the key performance indicators such as reperfusion rate within 12 hours since symptom onset, change of pre-hospital delay, changes of in-hospital delay time and in-hospital outcomes between the intervention groups and control groups, the effectiveness of the intervention measures was evaluated for further optimization. (see study design overview in Fig. 1)
Study regions and randomization
The study was carried out in 8 regions which represented various socioeconomic conditions as well as medical resource level in China. The regions were selected based on geographic location, urbanization, medical capacity to support timely treatment of STEMI. (Fig. 2) In addition, all these cities were willing to participate in the study to improve the treatment condition for STEMI patients. Stratified cluster randomization was performed according to the composite evaluation of the socioeconomic conditions, urbanization and medical capacity of the local regions. Guangzhou, Panyu, Shenzhen and Foshan regions were considered as developed area of medical capacity of STEMI treatment. Among them, Panyu and Foshan were randomized to the intervention groups while Guangzhou and Shenzhen were in the control group. Dongguan and Yangjiang were considered as the developing areas, Dongguan were randomized to the intervention group and Yangjiang were randomized to the controlled group. Maoming and Longyan were considered underdeveloped regions of medical capacity for STEMI treatment, of which Maoming were randomized to the intervention group and Longyan were randomized to the controlled group.
Patient enrollment
The major PCI centers of the study regions were included in the study to be in charge of local interventions of enhanced public education and regional network construction. (Listed in supplementary 1) Consecutive STEMI patients admitted to the PCI centers through the emergency department were included to evaluate the change of treatment delay. The diagnosis of STEMI must met the third Universal Definition for Myocardial Infarction. Relevant medical information were recorded and collected by the reception doctors, including time of symptom onset, time of arrival at the hospital, time of balloon dilatation. Patients were excluded if the timings of the treatment were missing. The treatment process is completely decided by the doctors in charge according to the patient's condition, without interference by the study enrollment.
Regional intervention group
Enhanced public education
Enhanced public health education for acute myocardial infarction was carried out in a variety of ways, including theme lectures in communities, brochures distribution, messaging education, push service of mobile applications, television and newspaper advertisement and so on. Cooperated with the local community medical service center, targeted education on the basic knowledge, self-identification, and key points for timely treatment of acute myocardial infarction were conducted. The frequency of education was determined according to the actual situation of each region, the content and attendance number were recorded after each education.
Regional network construction
The regional network construction included actions as follow: 1) training in the diagnosis and treatment of STEMI patients in primary and secondary hospitals, developing a unified and effective process of first medical contact; 2) construct the efficient “green” first-aid channel for STEMI treatment in PCI hospitals, shortening the delay time of door-to-balloon; 3) cooperated with the local 120 emergency center to establish a co-working network, which comprised of all the three-level hospitals in the region, and standardized route as well as procedure for prompt STMEI patients transfer. The practical implementation plan was carried out according to the actual situation of each region. For example, in order to improve the rate of early reperfusion therapy in regions where transfer of STEMI patients from first contact primary hospital to tertiary PCI hospital was too remote to complete within 2 hours, several primary hospitals will be selected to construct as a thrombolytic treatment unit for transitional reperfusion therapy.
Study outcomes and follow-up management
The study outcomes are as follows: the primary outcome was defined as reperfusion rate, defined as the proportion ratio of timely reperfusion with 12 hour since symptoms onset to revascularization among the whole enrolled population; secondary outcomes were defined as (1) change of pre-hospital delay of symptom onset to PCI hospital-arrival time; (2) Changes of in-hospital delay time, including door-to-balloon time; (3) in-hospital outcomes, including MACE events (consist of in-hospital death, stoke and recurrence of myocardial infarction), in-hospital death, and treatment withdrawal.. Telephone interviews or clinical interviews were conducted for all participated STEMI patients for at least 1 year (at 3, 6, 12 months since enrollment within the first year), and annual follow-ups were performed after that.
Data collection
Trained physicians or study nurses collected data with a data collection card during patients’ hospitalization by medical record review. Items of interest are 1) demography data, 2) preexisting risk factors and comorbidities, 3) medical treatments and interventions during hospitalization, 5) clinical complications, 6) medication before and during hospitalization and at hospital discharge, 7) symptom-onset to the first medical contact time, door-in-door-out time, door-to-balloon time, 8) laboratory information. The key timing data of STEMI onset and treatment are precisely recorded.
The timing of treatment, such as admission time, first ECG time, wire-crossing time of PCI treatment, were recorded in a STEMI patients data collection card by a medical staff alongside since the STEMI patients were admitted to the emergency department (Fig. 3). If the patient was transferred by the ambulance from emergency medical service, the patient and the paramedic on the ambulance would be asked for the timing record before the admission, such as the time to call the ambulance. The characteristic information of the patient's hospitalization is collected through the records of the hospital information system and entered into the electronic data capture system. The STEMI patients were followed up through outpatient service or telephone calls at 1month, 3 months, 6 months and 1 year, and the follow-up medication and adverse events were collected and entered into the electronic data capture system
Data management
Critical timing data of the STEMI treatment course were recorded on the STEMI timing data collection card. Once patients with chest pain were diagnosed with STEMI in the emergency department, clinical doctors started to record the information on the STEMI treatment timing according to the patients’ inquiry. The timings of STEMI treatment were recorded by the emergency doctors, the cardiologists, and the catheter surgeons or nurses respectively. The timing data collection cards were finally collected by the research assistants and the information integrity would be checked. If there was any information missing, the patient or relevant physician would be promptly asked to fill up. The assistant filled in the complete STEMI information card with the CRF and double-check to ensure that the information is accurate, and the STEMI information registration card is reserved for verification afterward.
Inpatient data of STEMI patients were recorded in the Hospital Information System (HIS) according to the routine medical treatment process. After discharge, all the STEMI patients’ case files were scanned and stored in the archive. Two research assistants recorded the in-hospital information of STEMI patients on the Clinical Research Form (CRF) based on the record of HIS files separately, checked the inconsistent data to verify the accuracy. When abnormal data was found, research doctors were promptly informed to retrieve the original data and make the correction. All the data recorded in the CRF were then entered on the online Electronic Data Capture (EDC) system. When the entry was completed, the data administrator would perform the database inspection and reported the abnormal data for inquiry, which consisted of content completion check, outlier data check, logical consistency check, etc. All the data with inquiry were inspected again to make sure veracity.
We established different methods for quality assurance. 1) Standard Operating Procedures (SOP) To reduce variability in data collection, all reporting institutions (hospitals, health departments) fill in all questionnaires according to standard operating procedures. 2) Data-Completeness All records are regularly checked for errors and inconsistencies. 3) Case-Reporting-Completeness To check the completeness of case reporting, we compared the number of all patients who were annually discharged from all the collaborating hospitals with a diagnosis of STEMI with the number of registered cases.
Data safety and confidentiality
All the data records, including the STEMI timing record card and the clinical research form, are encrypted and stored in the electronic data capture system, all medical staff members had to use their unique passwords to log into the online EDC system for data access. The paper data records were archived and stored in a special archive.
Sample size
Sample size of 4000 in the intervention group and 4000 in the control group, which were obtained by sampling 4 clusters with 1000 subjects each in the intervention group and 4 clusters with 1000 subjects each in the control group, achieve 83.475% power to detect a superiority margin difference between the group proportions of 0. The proportion in the intervention group is assumed to be 0.34 under the null hypothesis and 0.5 under the alternative hypothesis. The proportion in the control group is 0.34. The test statistic used is the one-sided Z-Test (Pooled). The intra-cluster correlation is 0.03, and the significance level of the test is 0.05
Statistical analysis
Continuous variables are represented in form of mean ± standard deviation or median and quartile according to whether they conform to a normal distribution, categorical variables are expressed in percentiles.Trends in baseline characteristics are tested using the Cochran-Armitage test for categorical variables and the Mann-Kendall test for continuous variables. To test for the in-hospital outcomes, the first year was considered as the reference, we constructed four indicator variables representing the following years, the time interval for each variable is 1 year. We performed logistic regression to test for in-hospital outcome, including indicators for time as key explanatory variables after adjusting for patients’ demographics, medical history, and clinical characteristics at admission. Odds ratios (ORs) and 95%CI from the multivariate logistic analysis related to the year indicators will be reported as well. Subgroup analysis of age, sex and different regions will be performed for additional exploratory analyses. All tests were two-tailed, p-values less than 0.05 are considered statistically significant. The statistical analyses would be performed using R software (version 3.1.2; R Foundation for Statistical Computing, Vienna, Austria).
Dissemination
Findings will be disseminated in future peer-reviewed papers and will inform strategies aiming at developing a collaborative regional network for STEMI management and education to reduce the delay time and STEMI mortality.
Patient and Public Involvement
The study involved no patient or public on the development of the research question, outcome measures, study design, recruitment, conduct and result dissemination.