“Missing” acute coronary syndrome hospitalizations during the COVID‐19 era in Greece: Medical care avoidance combined with a true reduction in incidence?

Abstract Background Reports from countries severely hit by the COVID‐19 pandemic suggest a decline in acute coronary syndrome (ACS)‐related hospitalizations. The generalizability of this observation on ACS admissions and possible related causes in countries with low COVID‐19 incidence are not known. Hypothesis ACS admissions were reduced in a country spared by COVID‐19. Methods We conducted a nationwide study on the incidence rates of ACS‐related admissions during a 6‐week period of the COVID‐19 outbreak and the corresponding control period in 2019 in Greece, a country with strict social measures, low COVID‐19 incidence, and no excess in mortality. Results ACS admissions in the COVID‐19 (n = 771) compared with the control (n = 1077) period were reduced overall (incidence rate ratio [IRR]: 0.72, P < .001) and for each ACS type (ST‐segment elevation myocardial infarction [STEMI]: IRR: 0.76, P = .001; non‐STEMI: IRR: 0.74, P < .001; and unstable angina [UA]: IRR: 0.63, P = .002). The decrease in STEMI admissions was stable throughout the COVID‐19 period (temporal correlation; R2 = 0.11, P = .53), whereas there was a gradual decline in non‐STEMI/UA admissions (R2 = 0.75, P = .026) following the progressively stricter social measures. During the COVID‐19 period, patients admitted with ACS presented more frequently with left ventricular systolic impairment (22.2 vs 15.5% control period; P < .001). Conclusions We observed a reduction in ACS hospitalizations during the COVID‐19 outbreak in a country with strict social measures, low community transmission, and no excess in mortality. Medical care avoidance behavior is an important factor for these observations, while a true reduction of the ACS incidence due to self‐isolation/quarantining may have also played a role.


| INTRODUCTION
The new coronavirus (SARS-CoV-2), which causes the coronavirus disease (COVID-19) is highly infectious and is responsible for the current pandemic. 1 Regardless of high or low SARS-CoV-2 penetrance among different countries, recommendations on social distancing/ self-confinement and drastic measures restricting the freedom of movement led to an unexpected social experiment for billions of people worldwide. At the same time that the global community was focusing on controlling the spread of COVID-19 with most countries rapidly redesigning their health services and enforcing unprecedented measures, worries arose about cardiac collateral damage. 2 Recent reports from countries highly impacted by the pandemic suggest a decline in acute coronary syndrome (ACS)-related hospitalization rates and primary percutaneous coronary intervention (PCI) activations, [3][4][5] while epidemiological findings from countries with either high or low COVID-19 incidence demonstrate variable population mortality rates, which do not always show a substantial increase compared to previous years. 6 Patients' avoidance of seeking medical care and more conservative ACS management by healthcare systems have been suggested as possible explanations for these observations. Additionally, an unexpected true reduction in the incidence of ACS due to the lack of environmental triggers as a result of the recommendations on social distancing, self-confinement, and drastic measures restricting the freedom of movement cannot be excluded and needs investigation.
We studied the rate of ACS admissions, treatment strategy, and outcomes during the COVID-19 outbreak compared to the corresponding period during the previous year in Greece, a country with low penetration of SARS-CoV-2 and no excess in overall mortality. Additionally, we assessed the impact of strict social measures on the observed ACS admission rate, and attempted to identify the presence of any cardiac collateral damage. The study complies with the Declaration of Helsinki and was approved by the local ethics committee at each hospital. Written approved consent was waived on the basis of the retrospective use of anonymized patient data.

| Study and control periods
The first confirmed COVID-19 case in Greece was identified on 26 February 2020 and by 2 March 2020, there were only seven confirmed cases. Therefore, we identified 2 March 2020 as the beginning of the COVID-19 period, and we studied the first 6 weeks of this period until 12 April 2020. During the 6-week period of the study, the Greek government authorities progressively imposed several measures of social distancing which also contributed to an increase in public awareness: (a) 10 March 2020: lockdown of all schools and universities and recommendation of self-confinement behavior; (b) 16 March 2020:80% of all business activities were locked down; and, ultimately, (c) 23 March 2020: drastic measures restricting the freedom of movement which continued until 3 May 2020. Until 13 April 2020 (ie, the end of our study period), there was a total of 2145 confirmed COVID-19 cases and 99 deaths in Greece. 7 To perform comparative analyses between the COVID-19 study period and a period without exposure to COVID-19, the corresponding period during the previous year (2 March 2019 to 12 April 2019) was used as control. Also, the study period was dichotomized to the time before (from 2 March 2020 to 22 March 2020; that is, the first 3 weeks of the study period) and after (from 23 March 2020 to 12 April 2020; that is, the last 3 weeks of the study period) the complete national lockdown, and comparative analyses were also performed for these two time periods during the COVID-19 outbreak.

| Statistical analyses
Categorical variables are presented as counts and percentages, and odds ratios (OR) with 95% confidence intervals (CI), and were compared using the chi-square or Fisher's exact test as appropriate. Continuous variables included in the analysis did not have a normal distribution and are summarized as median and interquartile range (IQR); comparisons were made using the Mann-Whitney test. Crude

| RESULTS
A total of 1848 ACS patients were included in the study (771 during the study period and 1077 during the control period). Detailed descriptive data of the population are presented in Table 1 and Appendix.

| ACS hospital admissions: comparison of COVID-19 to control period
The mean rate of ACS admissions in the study period (18.4/day) was significantly lower compared to the control period (25.6 admissions/ day; IRR: 0.72, 95% CI: 0.65-0.79, P < .001). Table 2 reports the mean admission rates per day for all ACS types; IRRs in the study period were also significantly lower for each ACS type compared to the control period. These data translate to an overall 28.4% reduction of ACS hospitalizations in the study period (24.5% for STEMI, 26.5% for NSTEMI, and 36.5% for UA; Figure 1).
On a weekly basis, there was a gradual decline in all ACS admissions reaching a minimum of 14 and 16 admissions/day in the fourth and fifth week corresponding to a relative reduction of 43% and 46%, respectively, whereas the minimum rate observed in any week in the control period was 23.9 admissions/day ( Table 2 and Figure 2A). After stratifying the incidence rate ratio (ie, the relative decrease in admissions) per week in the COVID-19 compared to the control period according to STEMI and NSTEMI/UA, we found that the decrease in STEMI admissions was stable throughout the COVID-19 period (temporal trend; P = .53), whereas there was a gradual decline in NSTEMI/ UA admissions (temporal trend; P = .026) ( Figure 2B). During the COVID-19 study period, a reduction in the number of ACS admissions from 429 to 342 was observed following the complete national lockdown restricting the freedom of movement compared to the period before the lockdown (ie, the last 3 weeks compared with the first 3 weeks in the study). The mean rate of ACS admissions after the lockdown (16.3/day) was significantly lower compared to the period before the lockdown (20.4 admissions/day; IRR: 0.80, 95% CI: 0.69-0.92, P = .002). The respective IRRs for the three ACS types (Table S1 in Appendix) indicated that the reduction after the lockdown was primarily due to a further decrease in NSTEMI T A B L E 1 Demographics, clinical characteristics, presentation, and angiographic data of patients admitted with ACS in the COVID-19 and control period

| In-hospital outcomes
In all ACS patients, there was a total of 54 in-hospital deaths (3%) sim-

| DISCUSSION
The main findings of our study are summarized as follows: frequently to the hospitals during the COVID-19 period; older patients were considered from the start of the outbreak as one of the population groups at highest risk from COVID-19 and were urged early by mass media and government authorities to avoid social contact and be self-confined. (c) During the COVID-19 outbreak, ACS patients presented more frequently with LV systolic impairment, which may serve as a surrogate marker for delayed MI presentation, and is supported by longer times from symptom onset to first medical contact observed for MI patients in other countries. [9][10][11] An alternative cause for the decline in the rate of ACS hospitalizations is a true reduction in the incidence of ACS. This could be attrib-  potentially how social life could be restructured so that triggering factors and the associated ACS incidence could be reduced.

| Limitations
The data presented are observational and no definitive conclusions can be drawn about causality. This is a retrospective study with all shortcomings associated with such an approach including the lack of additional variables of interest, which were not readily available. However, our study gathered comparative data over a 6-week period from the huge majority of hospitals with primary PCI services in the country, thereby providing representative information on ACS-related hospitalizations.

| CONCLUSIONS
We observed a decline in ACS-related hospitalizations during the COVID-19 outbreak in a country with low penetrance of SARS-CoV-2 virus, strict measures of social restrictions and no substantial increase in overall population mortality. Our findings provide indirect evidence that medical care avoidance behavior among ACS patients is an important factor for these observations, while a true reduction of the ACS incidence due to self-isolation/quarantining, and thus, a lack of environmental triggers for ACS, cannot be excluded. Further research is needed to clarify these factors.