Inuence of the First-wave COVID-19 Pandemic on Emergency Acute Coronary Syndrome: a Multicenter Retrospective Study From a Non-epicenter Region

Background: The COVID-19 pandemic presented severe challenges to emergency practice of acute coronary syndrome (ACS). However, poor evidence was shown on ACS in a non-hot-spot region. We sought to clarify the inuence of the rst-wave COVID-19 pandemic on emergency ACS from a non-epicenter region. Methods: This retrospective multicenter study was conducted in emergency ACS patients during the pandemic (from 2020-01-23 to 2020-03-29) and the ones during the same period in 2019. Clinical characteristics, timeline parameters and treatment strategies were compared between different groups. Association of the pandemic with non-invasive therapy was further assessed. Results: Compared with 2019, ACS had a drop in admission (267 cases vs. 475 cases) and invasive therapy (140 cases vs. 318 cases). Also, process delays were detected including the period from symptom onset to rst medical contact (S-to-FMC, 5h vs. 2.5h), the period from FMC to electrocardiogram (ECG) completed (8min vs. 4min) and the period from FMC to dual antiplatelet therapy (FMC-to-DAPT, 25min vs. 19min). Primary percutaneous coronary intervention (PPCI) decreased by 54.9% in STEMI and early invasive therapy decreased by 59.2% in NSTE-ACS. The proportion of invasive therapy in NSTE-ACS decreased more than in STEMI (16.9% vs. 10.1%) with longer process delay. The pandemic was associated with increased non-PPCI in STEMI (OR=1.707, 95%CI 1.082-2.692, P=0.021) and elevated medication in NSTE-ACS (OR=2.029, 95%CI 1.268-3.247, P=0.003), respectively. Conclusion: Even in a non-epicenter region, the rst-wave COVID-19 pandemic caused a signicant reduction of invasive therapy and evident process delays in emergency ACS. Coronavirus-2019 ACS: Acute coronary syndrome; STEMI: ST-segment-elevation myocardial infarction; NSTE-ACS: Non-ST-segment elevation acute coronary syndrome; PPCI: Primary percutaneous coronary intervention; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; Scr: Serum creatinine; FMC: First medical contact; S-to-FMC: Symptom onset to FMC; DAPT: Dual antiplalet therapy; IQR: Interquartile range; OR: Odds ratio; CI: Condence interval.


Introduction
Acute coronary syndrome (ACS) is one of the most common chest pain emergencies, including STsegment-elevation myocardial infarction (STEMI) and non-ST-segment elevation acute coronary syndrome (NSTE-ACS) [1]. Prognosis of ACS is highly dependent on standard procedures for chest pain emergency including early transfer, prompt diagnosis, risk strati cation and timely intervention [2]. Since the outbreak in December 2019, coronavirus-2019 disease (COVID-19) caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has rapidly spread to the worldwide and been a devastating viral pandemic [3,4]. As of August in 2021, a total of more than 210 million cases have been diagnosed and approximately 4.4 million con rmed deaths [5]. The COVID-19 pandemic posed severe burden and challenges to emergency network and rescue procedure.
Reasonable medical responses between COVID-19 prevention and revascularization are critical for rescuing emergency ACS [6]. After the rst-wave outbreak, the ndings from Europe revealed that hospital admissions for all types of ACS decreased by approximately 40%, meanwhile numbers of PCI procedures had an estimated 30%-40% reduction [7,8]. Similarly, the data from U.S. showed a 43.7% decline in hospitalizations during the rst-phase pandemic [9]. Previous evidences about the impact of the pandemic on ACS were still mostly concentrated in high-intensity epicenters [10]. However, poor evidence on clinical characteristics and intervention strategy remained for ACS in non-hot-spot regions; and fewer studies focused on the effect of the pandemic on non-invasive therapy in STEMI and NSTE-ACS, respectively. Moreover, it is also not clear that real pro le of ACS emergency during the rst-wave epidemic in the absence of mature experience.

Study population
This was a retrospective multicenter study with a total of 14 hospitals involved. The rst-wave COVID-19 pandemic was de ned as the period from January 23 to March 29 in 2020. On January 23 of Wuhan's lockdown, our city also raised local health response to curb the spread of the epidemic. During the pandemic, a total of 576 infection cases occurred in this region including 570 cured and 6 deaths; then public health response was downgraded on March 29 owing to complete clearance of infection cases ( Figure 1). In our study, emergency ACS patients during the same period in 2019 were also included to reduce the confounding effect of seasonal alternation and holiday events. In addition, the patients with con rmed or suspected COVID-19 were excluded. Our study protocol complied with the Declaration of Helsinki and was approved by Xinqiao Hospital Ethics Committee, Army Medical University. Emergency procedure during the pandemic All emergency patients were screened for SARS-COV-2 according to Clinical Guideline of Diagnosis and Treatment (7th edition) [11]. Based on fever symptoms and epidemiological history, admitted patients were rst assigned to emergency or fever clinics. With the assistance of COVID-19 expert team in hospital, the patients with con rmed or suspected COVID-19 would be transferred to the designated hospitals quickly. The patients without exclusion of COVID-19 temporarily would be transferred to special wards for isolation, and if further test was positive, they would be transferred to the designated hospitals as soon as possible. Whether to perform invasive therapy mainly depended on ischemic risk assessment and guideline recommendation [12,13]. The owchart of chest pain procedure was shown in Figure 2.

Data collection and de nition
Clinical data were obtained from medical records by trained clinicians in each hospital and were veri ed by another two investigators. Clinical characteristics included demographic data, admission signs, arrival periods, transferred methods, chest pain timelines and treatment strategy. Diagnostic criteria of ACS refer to the de nitions of European Society of Cardiology guidelines for NSTE-ACS and STEMI [14,15].Global Registry of Acute Coronary Events (GRACE) risk score is applied for prediction of risk in ACS and is calculated based on the clinical characteristics, electrocardiogram (ECG) performance and laboratory parameters at admission [16]. Transferred methods consisted of walk-in, in-hospital onset, emergency medical services and inter-facility transports; walk-in and in-hospital onset were deemed as nontransferred, while EMS and inter-facility transports were regarded as transferred. Chest pain timelines included the period from symptom onset to rst medical contact (S-to-FMC), the period from FMC to electrocardiogram completed (FMC to ECG completed), the period from door to troponin completed and the period from FMC to dual antiplatelet therapy (FMC to DAPT) [17]. The duration of early invasive therapy is within 24 hours.

Statistical analysis
Continuous variables are presented as mean ± SD for symmetric distributions and median (interquartile range, IQR) for skewed distributions. Categorical variables are expressed as frequency (percentage). For comparisons between groups, the t test was performed for symmetric distributed variables, and nonparametric Mann-Whitney U test was applied for skewed distributed variables. Differences in categorical variables were assessed by the Chi-squared test or Fisher exact test. Taking non-invasive therapy as the dependent variable, we conducted logistic regression analysis to evaluate the association of COVID-19 pandemic with non-invasive therapy, and then sub-group analysis was utilized to further examine this correlation. Two-tailed P values < 0.05 were considered statistically signi cant. All statistical analyses were performed using SPSS software version 24.0 (SPSS, Inc, Chicago, Illinois).

Clinical characteristics and therapy strategies in emergency ACS
A total of 742 emergency ACS patients with non-COVID-19 were enrolled in this study with 267 cases during the pandemic and 475 cases during the same period in 2019 (Table 1). Compared with 2019, ACS had a reduction in cases by 43.8% totally, while the cases of emergency STEMI and NSTE-ACS decreased by 47.8% and 38.1%, respectively. Moreover, there were no differences in admission signs, GRACE scores, arrival period and transferred method (P>0.05). Signi cant delays appeared in S-to-FMC (5.0h vs. 2.5h), FMC to ECG completed (8 min vs. 4min), door to troponin completed (13 min vs. 12min) and FMC to DAPT (25min vs. 19min) (P<0.05) ( Table 1).   (Table 3).   Association between the pandemic and non-invasive therapy in emergency ACS Logistic regression analysis was performed to explore the association of COVID-19 pandemic with noninvasive therapy in STEMI and NSTE-ACS. The results indicated the pandemic was associated with increased non-PPCI in STEMI (OR=1.707, 95%CI 1.082-2.692, P=0.021) and also correlated with elevated medication in NSTE-ACS signi cantly (OR=2.029, 95%CI 1.268-3.247, P=0.003). Sub-group analysis further recon rmed this correlation (Table 5). Furthermore, compositions of ACS and therapy strategy were shown in Figure 3.

Discussion
Our study found that ACS had signi cant delays in emergency procedure and an apparent drop in invasive therapy; the pandemic was associated with increased non-invasive therapy, especially for NSTE-ACS.
ACS often has acute chest pain as the onset symptom and further leads to heart failure, arrhythmia and even cardiac arrest [18]. Early identi cation and intervention for ACS contributes to improve cardiovascular outcomes, thus chest pain emergency is established to cope with these conditions [19].
Under a uni ed procedure, ACS patients are diagnosed, transferred and treated through chest pain emergency to reduce ischemic risk [20]. In STEMI, PPCI is generally recommended as priority while sometimes thrombolysis could be also considered as supplement to ensure timely reperfusion [21]. In NSTE-ACS, therapy strategy is mainly based on evaluation of ischemic risk; high-risk patients including hemodynamic instability, recurrent or refractory chest pain, malignant arrhythmia and severe heart failure should perform early invasive treatment within 24 hours or even 2 hours; medication could be considered to be optional for "relatively stable" patients [22]. COVID-19 not only directly increased cardiovascular risk through biological mechanisms, but also affected the prognosis of ACS patients by disrupting conventional treatment procedure [23]. Although previous studies provided some evidence of the pandemic's impact on ACS, this impact still remained unclear and unquanti ed in a non-epicenter.
Our ndings rstly revealed decreased admissions and signi cant process delays after the rst-wave epidemic. In hot-spot regions, similar results were also reported but larger reduction of hospitalization occurred in NSTE-ACS [24,25]. However, changes in ACS composition were not observed in our study maybe ascribed to relatively low-intensity epidemic and active admission. We proposed the main explanations for the decline in hospitalization. Firstly, the patients preferred to social distancing and medical avoidance owing to fear of infection. Secondly, strict social restrictions were not conducive for patients to obtain timely medical assistance at symptom onset. Thirdly, conventional treatment-oriented mode was transformed into epidemic control-oriented mode in medical institutions that meant more resources were spent on epidemic management thus the capacity for treatment might be weakened. Of  [31]. Likewise, our study found both PPCI for STEMI and early invasive treatment for NSTE-ACS dropped signi cantly. PPCI was still the preferred option for reperfusion in STEMI from our region rather than thrombolysis that also exhibited good adaptability of catheter-labs to the epidemic. Consistent with process delays, the proportion of invasive therapy in NSTE-ACS declined more than in STEMI suggesting conservative therapeutic behaviors. For STEMI, non-PPCI was more severely affected by the pandemic manifested as few thrombolysis and serious in-hospital delays that implied considerable non-PPCI patients rejected basic reperfusion therapy. This might be due to frequent informed risks and excessive protective measures in hospital, which further increased anxiety and insecurity of patients and reduced medical compliance. The absence of thrombolysis as supplement for PPCI would greatly increase the risk of life-threatening adverse events, thus it is essential for STEMI rescue to optimize in-hospital procedure [32]. Moreover, our study further indicated whether STEMI or NSTE-ACS, the pandemic increased the probability of non-invasive therapy in a non-epicenter. This surge in non-invasive strategy derived from both patient-level and hospital-level. On the one hand, patient's decision on treatment become more negative subjected to individual psychology affected by the pandemic; on the other hand, decision-making from hospital tended to be cautious in treatment based on prevention of nosocomial infections and lack of medical resources. As a non-hot-spot region under the rst-wave epidemic, our ndings might provide references for emergency ACS practice to other current non-epicenters.
Our study had several limitations. First, this study was subject to the biases inherent to its retrospective design. Second, clinical characteristics and timeline parameters were assessed by trained physicians in each center without central recon rmation, potentially resulting biases and errors. Third, our study had a relatively small sample size and no longitudinal analysis. Fourth, the absence of PPCI parameters limited further analysis for mechanical reperfusion procedure. Last, it remained unclear how local policies of each hospital had altered due to the rst-wave pandemic that might affect emergency procedure for chest pain.

Conclusions
Even in a non-epicenter region, a signi cant reduction occurred in invasive therapy with evident emergency process delays for ACS. In current epidemic, emergency procedure should be appropriately adjusted and considered for integration into chest pain practice. Flowchart of emergency procedure