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In-depth look into urban and rural disparities in prehospital delay in patients with acute ST-elevation myocardial infarction and its impact on prognosis: a prospective observational study

Objectives In line with the cardiac fast track, the ‘green pathway for patients with heart attack’ policy in China is implemented to reduce door-to-balloon time in patients with ST-segment elevation myocardial infarction (STEMI). However, the difference in prehospital delay between urban and rural areas of China and its impact on prognosis is unclear. Design Prospective observational study. Setting This study was conducted in a tertiary hospital, the only nationally accredited chest pain centre with percutaneous coronary intervention (PCI) capacity in Pizhou, China. Participants 394 patients with STEMI without patients with in-hospital STEMI or patients lost to follow-up were included. Primary outcome measures Primary outcome was major adverse cardiovascular events (MACEs), including cardiac death, non-fatal myocardial infarction and heart failure. Results Among 394 patients enrolled, 261 (66.2%) were men, the median age was 69 years (interquartile range: 61–77 years), and 269 (68.3%) were from rural areas. Symptom-to-door (S2D) time was significantly longer for rural patients than for urban patients (p<0.001). Cox regression analyses revealed living in rural areas was independently associated with prolonged S2D time (adjusted HR 0.59; 95% CI 0.43 to 0.81; p=0.001). HR of <1 indicates that the S2D time is longer for patients in the rural group (group of interest). During 1-year follow-up, the incidence of MACEs was higher in rural patients (p=0.008). The unadjusted OR for MACEs between rural and urban patients was 2.22 (95% CI 1.22 to 4.01). Adjusting for sex did not attenuate the association (OR 2.06; 95% CI 1.13 to 3.76), but after further adjusting for age, cardiac function classification, S2D time and performance of primary PCI, we found that odds were similar for rural and urban patients (OR 1.19; 95% CI 0.59 to 2.38). Conclusions Rural patients with STEMI had a longer S2D time, which led to a higher incidence of MACEs. This study provides rationales for taking all the measures to avoid prehospital delay.


INTRODUCTION
ST-segment elevation myocardial infarction (STEMI) is the most common acute manifestation of coronary heart disease, with high morbidity and mortality. 1 The Global Registry of Acute Coronary Events showed that STEMI accounted for one-third of coronary events. 2 In China, the proportion of hospitalised STEMI patients has been increasing year by year. 3 Therefore, STEMI is a major public health problem, seriously threatening human life and bringing very large economic burdens to both families and society. In recent years, with the progress of medical treatment and preventive measures, the mortality and complication rates have been reduced in patients with STEMI. [4][5][6][7] The time from symptom onset to culprit vessel

STRENGTHS AND LIMITATIONS OF THIS STUDY
⇒ We constructed six models to determine the association between rural area and incidence of major adverse cardiovascular event and to extrapolate the potential disparity between rural and urban areas. ⇒ A multivariable Cox proportional hazards model was constructed from symptom-to-door (S2D) time by rural/urban areas, in which the occurrence of STsegment elevation myocardial infarction was defined as the event, and the S2D time was considered as the survival time. ⇒ The limitation of this study is that the results of this single-centre observational study might not represent the actual situation of China as a whole. ⇒ Since the baseline characteristics were balanced between the patients who were followed up and those who lost to follow-up, the rate of loss to follow-up may only have a slight influence on the results.
Open access reperfusion has also been greatly reduced since fast heart attack care is promoted globally. 8 In line with the cardiac fast track, the 'green pathway for patients with heart attack' policy is implemented in China. With the acceleration of chest pain centre construction, the treatment of acute myocardial infarction in China, especially the door-to-balloon (D2B) time, is improving. 9 10 However, the prehospital delay in patients with STEMI has never been thoroughly investigated in China. Although the number of rural residents has decreased due to industrialisation and urbanisation in China, there are still a large number of people living in rural areas, especially elderly people. 11 People in rural areas have relatively poor knowledge of the disease, less efficient transportation facilities and lower levels of primary care. 12 13 To provide a theoretical basis for spreading the accredited chest pain centre further down to the rural front line and optimising the management algorithm of patients with chest pain, this study aimed to explore the urban and rural disparities in prehospital delays in patients with STEMI and their impact on prognosis.

Study design and population
In this prospective observational study, all acute patients with STEMI who were admitted to the Pizhou Affiliated Hospital of Xuzhou Medical University (Pizhou Hospital) from January 2018 to June 2020 were included. This hospital is the only nationally accredited chest pain centre with percutaneous coronary intervention (PCI) capacity in the Pizhou, a region of 2088 square kilometres and 1.46 million people. STEMI was diagnosed in accordance with the universal definition of myocardial infarction. 14 All the patients were divided into the rural group and the urban group based on their location where STEMI occurred. Based on the 2014 Administrative Planning approval document of Pizhou City, Jiangsu Province, China, their location was classified into urban or rural areas. In detail, Yunhe subdistrict, Donghu subdistrict, Paoche subdistrict and Daiwei subdistrict were designated as urban areas, and the remaining areas of Pizhou were rural areas. Patients with in-hospital STEMI or patients who were lost to follow-up were excluded from this study.

Data collection
Sociodemographic characteristics (age, sex and education level) and clinical characteristics (cardiovascular comorbidities, smoking, drinking, previous medical history and cardiac function classification) were collected. Based on the highest level of education completed by the participants, the education level was classified as below high school or high school or above. The estimates of delays, including symptom-to-door (S2D) time and D2B time and transportation distance, were based on data registered in the national chest pain centre reporting platform. In our study, prehospital delay was defined as S2D time, that is, time from symptom onset to arrival at Pizhou Hospital.
Therefore, the prehospital delay consists of patient delay (time from symptom onset to first medical contact) and prehospital system delay (time from first medical contact to arrival at the PCI centre). The location where STEMI occurred was self-reported by patient. Transportation distance was defined as the distance from the patient's location where the STEMI occurred to Pizhou Hospital. In addition, information on pretreatment with fibrinolysis and the performance of primary PCI (PPCI) was collected. The first-visit medical institutions of the patients were categorised into primary healthcare centres and tertiary hospitals according to the Chinese hospital classification system.

Clinical outcomes and follow-up
The primary endpoint was major adverse cardiovascular events (MACEs), which included cardiac death, non-fatal myocardial infarction and heart failure. The secondary endpoints were cardiac death, non-fatal myocardial infarction, heart failure, in-hospital death and all-cause death. The time and cause of death were obtained from the self-report of the patient's relatives or Xuzhou Centers for Disease Control and Prevention database. All patients received standard of care after discharge. Follow-up was completed via clinic visits or by telephone interviews with patients or their relatives every 3 months after discharge within 1 year. If a patient had an outcome event during follow-up, all his/her medical records were acquired and adjudicated.

Statistical analysis
All the continuous variables investigated in our study were non-normally distributed and presented as medians and interquartile ranges (IQRs). Differences between groups were tested using the Mann-Whitney U test. The categorical variables were expressed as counts with percentages and were compared using the χ 2 test or Fisher's exact test, as appropriate. Statistical significance was considered when two-sided p values <0.05.
A multivariable Cox proportional hazards model was constructed from S2D time by rural/urban areas. At the first step, the association between S2D time and all variables that were considered to have a potential influence on S2D time was tested univariate analysis. Then, those variables with a p value <0.05 in univariate analysis were adjusted in the multivariable Cox proportional hazards model (enter method). HRs and their corresponding 95% CIs were used to estimate the association (online supplemental method).
Multivariable logistic regression was performed to determine the risk factors associated with the incidence of MACEs. Variables with a p value <0.01 in univariate analyses were included in the multivariable logistic regression model. An additional multivariable logistic regression was performed to estimate the association of rural areas and incident MACEs. The ORs and the corresponding 95% CIs were obtained to assess the association. All analyses were performed using SPSS statistical software V.22.0.

Patient and public involvement
Patients and the public were not involved in the design, conduct reporting or dissemination plans of our research.

RESULTS
Baseline demographic characteristics A total of 418 acute patients with STEMI were admitted to Pizhou Hospital during our study period. Our final analysis included 394 patients who fulfilled the inclusion and exclusion criteria. Figure 1 depicts the patient flow through the study. In total, the median age was 69 years (IQR: 61-77 years), and 261 (66.2%) of the patients were men. Table 1 shows the baseline characteristics of all 394 patients. Compared with those in the urban group, patients in the rural group were older and more likely to be women and poorly educated. Our study group and the group of patients lost to follow-up were balanced with respect to all the baseline characteristics (online supplemental table 1). Table 2 shows that S2D time was significantly longer for patients in the rural group than for those in the urban group (190 min vs 75 min, p<0.001). The transportation distance from the patient's location where the STEMI occurred to the tertiary hospital with PPCI capacity (Pizhou Hospital) was longer for patients in the rural group than for those in the urban group (23.3 km vs 4.5 km, p<0.001). Patients in the rural group were less likely to go to Pizhou Hospital for their first medical visit than were those in the urban group (27.5% vs 48.8%, p<0.001). Patients in the rural group were more likely to miss the PPCI indication (13.4% vs 4.0%, p=0.005). The proportion of patients who underwent PPCI was significantly lower in the rural group than in the urban group  Open access (75.1% vs 91.2%, p<0.001). There was no significant difference in D2B time between the two groups. Notably, thrombolytic therapy was not performed in any of the patients in the entire cohort. Cox regression analyses revealed that patients in the rural group had significantly longer S2D times than those in the urban group (crude HR, 0.46; 95% CI 0.37 to 0.57; p<0.001). An HR of <1 indicates that the S2D time is longer for patients in the rural group (group of interest) than for those in the urban group (reference group). Variables including sex, age, education level, transportation distance and first-visit to a medical institution other than Pizhou Hospital were significantly associated with S2D time (online supplemental table 2). After adjusting for these variables, the association between rural area and S2D time remained statistically significant (adjusted HR, 0.59; 95% CI 0.43 to 0.81; p=0.001) (table 3).

Major adverse clinical events during the one-year follow-up
During the 1-year follow-up, MACEs occurred in 66 patients in the rural group (24.5%, 66/269) and 16 patients (12.8%, 16/125) in the urban group (p=0.008). As shown in figure 2, no statistically significant difference was observed in the incidence rates of cardiac death, nonfatal MI and heart failure between the two groups. The allcause mortality of the rural group was significantly higher than that of the urban group (17.8% vs 8.8%, p=0.019). Independent predictors of MACEs in the entire study population were older age, Killip class ≥II and prolonged S2D time (online supplemental table 3). Table 4 shows that, when rural patients and urban patients were compared, the unadjusted OR for MACEs after STEMI was 2.22 (95% CI 1.22 to 4.01). Adjusting for women did not attenuate the association (OR, 2.06; 95% CI 1.13 to 3.76), but further adjusting for age attenuated the association between rural areas and MACEs (OR, 1.66; 95% CI, 0.89 to 3.08). After additional adjustment for the cardiac function classification, S2D time and performance of PPCI, the odds were similar for rural and urban patients (OR, 1.19; 95% CI 0.59 to 2.38).

DISCUSSION
Our study is the first to investigate the urban and rural disparities in prehospital delay in patients with acute STEMI and their impact on the prognosis of STEMI in China. The major findings are as follows. Although the D2B time was similar between the two groups, the S2D time was significantly prolonged in patients from rural areas compared with those in urban areas; in the rural

Open access
group, patients had a higher proportion of missed PPCI indications and were less likely to receive PPCI; and a higher 1-year incidence rate of MACEs was observed in the rural group than in the urban group. This disparity could be explained by age, cardiac function classification, S2D time and PPCI performance. The 2017 European Society of Cardiology Guidelines emphasised the total ischaemic time of STEMI, raising the concept of entire rescue time, which consists of S2D time and D2B time. According to the recommendation from the 2017 European Society of Cardiology guidelines, a PPCI is not indicated in patients with time from symptom onset >12 hour and without clinical and/or electrocardiographic evidence of ongoing ischaemia. 15 A reduction in D2B time is significantly associated with a decrease in mortality, 16 17 and measures have been taken to reduce D2B time. 18 19 With the establishment of chest pain centres in China in the past decade, the D2B time was greatly reduced to within 60-90 min. 10 However, a further decrease in D2B time from 83 min to 67 min had no association with a reduction in in-hospital mortality. 20 In our study, the D2B time was approximately 80 min, and there was no difference in in-hospital mortality between the two groups. However, the 1-year clinical outcome was markedly different. This difference is attributed to the entire myocardial ischaemic time. To reduce the entire rescue time, the possibly shortened duration is S2D time.
Indeed, in our study, the S2D time of patients with STEMI in the rural group was much longer than that of the urban group. There are four possible reasons accounting for this prehospital delay. Poor family care: our study showed that patients with STEMI from rural areas were older. Such senior patients in rural China lack good family care because their adult children move to cities or coastal areas to seek better employment opportunities. 21 We acknowledge that old age is an independent predictor of MACEs and all-cause mortality, 22 but poor family care is the hurdle to receiving quick first-aid service when older patients are in need. Lacking disease awareness: the most important factor influencing the awareness of disease was  educational level, followed by age. 23 From the baseline characteristics of our observation, the rural patients had a lower educational level and older age. Their insufficient understanding and misjudgement of early symptoms of STEMI 24 prolonged the prehospital time and missed the best opportunity for revascularisation. Access to medical resources: the accessibility of high-quality medical facilities has a conceivable impact on the treatment of patients. Compared with urban patients, rural patients lack highquality medical resources. 25 The nearest medical facilities for rural patients with STEMI are village clinics and town hospitals that do not have the capability of PPCI. Patients have to be transported to large tertiary hospitals after diagnosis. In our study, rural patients had higher referral rates than their urban counterparts did. Notably, none of the patients initially underwent thrombolytic therapy before admission to tertiary hospitals. Transportation distance and facilities: The distance between the residence of rural patients and hospitals qualified for PCI was significantly longer than that of urban patients according to our observation. Although the average distance of 23 km is not very long in modern society, the facilities for rural patients to use are insufficient. Less frequent public transportation, less ownership of private vehicles and less efficient cabs or ambulances are responsible for these delays. The prolonged S2D time in the rural group could contribute to rural patients missing the PPCI indication and indirectly lead to a lower proportion of patients receiving PPCI. Previous studies have demonstrated that elderly, female and poorly educated patients were less likely to receive reperfusion therapy. 26 27 These are exactly the characteristics of the rural patients with STEMI in our study.
Early opening of infarcted vessels is the key point for STEMI and is crucial for improving the prognosis of patients with STEMI. 28 29 A previous study demonstrated a 7.5% increase in annual mortality for every 30 min delay in successful reperfusion. 30 Our study showed that the S2D time was significantly longer than that of urban patients, which led to a significantly higher incidence of MACEs and mortality in rural patients than in urban patients. In our study, the in-hospital mortality of the entire study population was 4.31%, which was close to the average level reported previously, 31 suggesting that the in-hospital algorithm and the management of patients with STEMI are in line with guideline-directed medical therapy. In this study, no difference in in-hospital mortality between the two groups was found, which might be due to the small sample size.
Prehospital delays are highly associated with the outcomes of patients according to the results of this study. This provides evidence for further optimising the workflow of emergent management of patients with STEMI. While emphasising the in-hospital management algorithm, we should extend our strength to prehospital management, especially in rural areas of China. Patients' awareness of STEMI symptoms and reperfusion procedures should be raised and treatment compliance should be further improved by strengthening propaganda and education among villagers. This is the first step towards reducing prehospital delays. Second, primary medical institutions should carry out thrombolytic therapy as an emergency treatment. This is an important step to shorten the total ischaemic time and improve the prognosis of patients with STEMI. Third, in order to alleviate the shortage of first-aid tools and improve the first-aid system in rural areas, more ambulances should be equipped. Moreover, the intelligent construction of village clinics is also a crucial link in the 'last mile' of prehospital treatment for acute myocardial infarction in rural areas. Primary medical treatment and emergency treatment will be connected with regional large comprehensive hospitals through installation of wireless electrocardiograph equipment and construction of an online medical network platform to achieve the 'sinking of high-quality medical resources to remote areas'. When the older patients with hurdle of receiving quick first-aid service, they can call the emergency medical telephone. The nearest village doctor can reach the patient and perform ECG, which can be transmitted to the PCI hospital diagnosis centre wirelessly for rapid diagnosis of the disease. If STEMI is highly suspected, village doctors can promptly pretreat the patients with antiplatelet drugs, and at the same time, call an ambulance and send the patients to the PCI centre for reperfusion therapy. In this way, barriers of receiving medical service for older patients will be resolved and referral efficiency will be improved. These measures play important roles not only in the treatment of acute myocardial infarction patients but also in the improvement of public health services and other emergent treatments in rural areas.
This study has several limitations. First, it was a singlecentre observational study, and the overall sample size was relatively small. Furthermore, long-term follow-up and a larger sample size are needed to validate the results of this study. Second, the population in this study is from the developed plain area of China. Our results might not represent the actual situation of China as a whole. However, the large 'gap' in the management of patients with STEMIbetween urban and rural areas could not be underestimated. Third, the proportion of patients lost to follow-up was 4.8%, which may influence our results. However, the baseline characteristics were balanced between the patients who were followed up and those who lost to follow-up.

CONCLUSIONS
Compared with urban patients, rural patients with acute STEMI had a prolonged prehospital delay, which led to a higher incidence of MACEs. This study provides rationales for taking all the measures to avoid prehospital delay by spreading chest pain units down to the rural front line through an online platform. Strengthening the propagation and education of knowledge regarding chest Open access pain and advanced treatment to rural dwellers and village doctors is also necessary.
Contributors M-LC, ML and YY participated in the design of this study. JW, JY and PL record all the cases. CS, CL, ZW and YL collected and performed the statistical analysis. CS wrote the first draft of the manuscript. CL revised the manuscript. M-LC and ML monitored the study. All authors provided input on data analysis, interpretations and participated in multiple revisions of the manuscript, approved the final version of the manuscript, and agreed to be accountable for all aspects of the work. Guarantor: M-LC. Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not applicable.
Ethics approval This study was approved by the Clinical Research Ethics Committee of The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China (XYFY2021-KL141-01) on 22 June 2021. This was an observational study and we did not intervene in patients. The estimates of delays were based on data registered in the Chinese chest pain centre reporting platform. All patient data were anonymously used with approval from the Clinical Research Ethics Committee of The Affiliated Hospital of Xuzhou Medical University. We did not use the patient's tissue, blood and other samples. Patients provided the written consent before primary percutaneous coronary intervention and no more additional interventional therapy was applied during the procedure.
Provenance and peer review Not commissioned; externally peer-reviewed.
Data availability statement Data are available upon reasonable request. The data that supports the finding of this study are available from the corresponding author upon reasonable request.
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