Gender Differences in Admissions and In-Hospital Outcomes of Patients With Acute Coronary Syndromes During the Coronavirus Disease 2019 Pandemic

Background The incidence of acute coronary syndromes (ACS) decreased during the coronavirus disease 2019 (COVID-19) pandemic. Few studies have investigated gender differences in ACS admissions and outcomes during pandemics and have presented divergent results. This study aimed to investigate the effect of the COVID-19 pandemic on male and female hospitalizations and in-hospital outcomes in patients presenting with ACS. Methodology We designed a retrograde, single-center trial gathering data for ACS hospitalizations during the lockdown (March 9, 2020, to April 30, 2020) compared with the same timeframe of 2019. ACS hospitalizations were subgrouped as ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), and unstable angina (UA). We calculated the incidence rate ratio (IRR) to compare all-ACS and subgroups for male and female hospitalizations and the risk ratio (RR) to compare overall male/female mortality. Results This study included 321 ACS patients (238 males, 83 females) during the COVID-19 lockdown and 550 patients (400 males, 150 females) during 2019. The IRRs of all-ACS/males/females were significantly lower during the COVID-19 period at 0.58 (95% confidence interval (CI) = 0.44-0.76), 0.59 (95% CI = 0.43-0.75), and 0.55 (95% CI = 0.37-0.74), respectively. The IRR for STEMI was significantly lower among females (0.59 (95% CI = 0.39-0.89)), but not among males (0.76 (95% CI = 0.55-1.08)) The IRR for NSTEMI was not significantly lower, meanwhile it was significantly lower for UA among both males and females. The overall ACS mortality increased during the COVID-19 period (7.4% vs. 3.4%; RR = 2.16 (95% CI = 1.20-3.89)). Important increase was found in males (7.45% vs. 2.5%; RR = 3.02 (95% CI = 1.42-6.44)), but not in females (7.2% vs. 6%; RR = 1.20 (95% CI = 0.44-3.27). Conclusions The admissions of ACS reduced similarly in males and females during the COVID-19 pandemic. The admissions of STEMI reduced predominantly in females. We identified a substantial increase in the overall ACS mortality, but predominantly in males, reducing the differences between males and females. Further studies are necessary to better understand the increase in male mortality during the pandemic.


Introduction
Studies from all over the world have documented an important reduction in admissions and related invasive procedures in patients with acute coronary syndromes (ACS) during the first wave of the coronavirus disease 2019 (COVID-19) pandemic [1][2][3][4][5][6][7][8]. During this period, worldwide, highly restrictive measures (physical distancing and periods of total lockdown) were adopted to prevent the spread of the virus.
To date, studies regarding the influence of gender on ACS admissions and treatment document that females, especially those diagnosed with acute myocardial infarction (AMI), present later in hospital from symptom onset [13,14] due to various factors, including social and psychological factors [15,16].
Few studies have been conducted to investigate the gender differences in patients hospitalized with ACS during the COVID-19 pandemic with divergent results regarding the admission frequency, invasive procedures, and outcomes [3,[17][18][19]. Therefore, we undertook this study to investigate the gender differences in hospitalizations and in-hospital outcomes of patients with ACS during the COVID-19 pandemic.

Materials And Methods
We designed a retrospective, single-center trial by gathering data for ACS hospitalizations during the lockdown (March 9, 2020, to April 30, 2020) compared with the same timeframe of 2019. ACS hospitalizations were subgrouped as STEMI, non-STEMI (NSTEMI), and unstable angina (UA). STEMI was diagnosed using the Fourth Universal Definition of Myocardial Infarction criteria [20]. Non-ST-elevation ACS were diagnosed according to the European Society of Cardiology (ESC) 2019 guidelines [21]. The study complies with the Declaration of Helsinki. Informed consent was waived because of the retrospective nature of the study.
Basal characteristic data including age and gender; cardiovascular risk factors including hypertension, type 2 diabetes mellitus, dyslipidemia, and smoking; comorbidities including previous coronary artery disease (CAD) (prior myocardial infarction, percutaneous or surgical coronary revascularization), dilated cardiomyopathy, stroke, and impaired renal function were collected. All coronary angiographic data including the stenotic vessels (stenosis over 50% of diameter), the number of stenotic vessels, vessels with no significant stenosis, and all revascularization procedures including percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG) were collected and analyzed.

Admission and in-hospital outcomes
The primary outcomes were overall and weekly IRR of all-ACS and subgroups (STEMI, NSTEMI, UA) admissions and related invasive procedures, in-hospital all-cause mortality, and cardiogenic shock (CSH), respectively, for males and females between the COVID-19 lockdown and control periods. Secondary outcomes were differences between periods for each gender including cardiac troponin I (cTnI) on admission (normal values = 0.00-1.00 ng/mL), time from symptom onset to intensive care unit (ICU) admission, time from ICU admission to sheath insertion, and left ventricular ejection fraction (at discharge).
We calculated the percentage of changes in the overall rate of admissions for ACS and related procedures, as well as the percentage changes in weekly ACS admission comparing the lockdown and control periods. The weekly percentage changes were calculated for seven weeks (March 9 to April 26, 2020) for both periods.
The rate ratio for different genders of all-ACS and subgroups (STEMI, NSTEMI, UA) admissions/procedures between the lockdown and the control period are shown as incidence rate ratios (IRR) which were calculated by comparing the incidence ratios of all-ACS and subgroups (STEMI, NSTEMI, UA) admissions or procedure/day during both periods. IRR is presented as 95% confidence intervals (95% CIs). The ratios of different genders for all-ACS deaths and CSH rate (in percentage) between the study and control periods are shown as RRs with 95% CIs.

Statistical analyses
Continuous variables regarding demographic characteristics, procedural, and hospital outcomes are presented as mean ± standard deviation (SD) and compared using t-test. Categorical variables are represented as percentage and RR with 95% CI and compared using the chi-square (χ 2 ) test. Poisson regression (STEMI admissions per week model) was used to calculate the IRR for male and female admissions and procedures between the lockdown and control periods. IRR between the groups is presented as 95% CI. A two-sided p-value of <0.05 was considered statistically significant. The statistical analysis was performed using SPSS version 21 (IBM Corp., Armonk, NY, USA).

Patients characteristics
Overall, 871 patients admitted with the diagnosis of ACS were included in this analysis. Of them, 638 were males (73.3%). In total, 238 were hospitalized during the lockdown and 400 during the control period; and of the 233 (26.7%) females, 83 were hospitalized during the lockdown and 150 during the control period. General characteristics are shown in Table 1. There were no differences between patients hospitalized during the lockdown and control periods both in males and in females regarding age and cardiovascular risk factors.

Gender differences in hospitalizations for ACS during the COVID-19 lockdown and control periods
The reduction in overall ACS was observed to be 40.5% in males and 44.7% in females. (Figure 1) The weekly IRR in hospitalizations for ACS during the lockdown and study periods both in males and females was statistically significant (0.60, 95% CI = 0.43-0.75, p < 0.001; and 0.55 (95% CI = 0.37-0.77, p = 0.001, respectively) ( Figure 2 and Table 2). Admissions for males and females according to the ACS type, coronary angiography, and PCI during the lockdown and control period are shown in Table 1 and Figure 1. The IRR for STEMI was significantly lower among females (0.59 (95% CI = 0.39-0.89)), but not in males (0.76 (95% CI = 0.55-1.08)). The IRR for NSTEMI was not significantly lower for both males and females (0.68 (95% CI = 0.41-1.08; and 0.70 (95% CI = 0.36-1.19), respectively), meanwhile, for UA, it was significantly lower for both males and females. The greatest fall in all-ACS admissions was observed during the third week for females (-71.3%) and the fourth week for males (-66.1%) during the pandemic outbreak ( Figure 2).   The proportion of male STEMI hospitalizations was considerably higher during lockdown compared to the control period (50.8% vs. 39.5%; p = 0.001), meanwhile, hospitalizations for UA reduced (28.6% vs. 43%; p < 0.001; Table 1). There were no differences in the proportion of female admissions with STEMI, NSTEMI, and UA between the study and control periods.
There were no significant differences in the percentage of male and female patients undergoing coronary angiography, PCI, and CABG between the two periods. Even though for the recommended CABG, a greater proportion of male patients compared to females was observed in both periods at 21.2% versus 13%, respectively, during the COVID-19 period and 20.3% versus 12.6%, respectively, during 2019 ( Table 1).
The frequency of three-vessel disease (46.3% versus 33.3%; p = 0.003) was greater among male patients during the lockdown period. No differences were observed regarding the frequency of vessel disease in female patients ( Table 1).

In-hospital outcomes
The symptom onset to ICU admission duration was significantly higher during the lockdown than the control period both in males (

Discussion
In Albania, previous studies have documented that the admissions for ACS, subgroups, and related invasive procedures declined significantly during COVID-19 compared to the control period (2019), associated with a 2.4-fold increase in in-hospital deaths [11,12]. In this study, reduction in ACS was observed in both males and females (-40.5%, p = 0.002, and -44.7%, p = 0.001, respectively). A significant reduction was observed in UA among both males and females (-60.5% and -50.6%, respectively), and only in female STEMI admissions (-40.7%). The greatest decline in hospitalizations for males and females was observed during the second to the fifth week following the pandemic outbreak. Moreover, important reductions were observed in males and females in coronary angiography and PCI procedures. Similar proportions of males and females undergoing coronary angiography and PCI during both periods were observed because there were no changes in ACS/STEMI revascularization protocols during the COVID-19 pandemic lockdown in our center. A significant increase in in-hospital mortality and CSH in male patients admitted during the COVID-19 period was observed.
Our results are consistent with studies reporting a reduction in ACS admissions among males as well as in females. Barbero et al. found a significant reduction in overall ACS admissions in 15 hospitals in Northern Italy in an inter-year analysis by 42% for females and 24% for males [17].
In our view, the possible explanations of the reduction among both males and females are the fear of catching the virus in medical establishments, the call of self-isolation, and physical distance from the authorities leading to refusing or not seeking medical care. Another possible explanation is the reduction of physical activities during the lockdown period, reducing the possible triggers for myocardial ischemia, followed by a reduction in ACS admissions.
The greatest reduction in both males and females was observed in UA admissions. A change in the profile of admitted patients was observed, mainly among male patients. The proportion of male hospitalizations with STEMI was significantly higher during lockdown (50.8% versus 39.5%; p = 0.001), whereas admissions for UA were lower (28.6% versus 43%; p < 0.0001) compared to 2019 ( Table 1). This can be explained by the fact that those who presented at the hospital to receive medical care were in more severe conditions and presented with more symptoms during the pandemic. On the other hand, other studies have presented divergent results. Mesnier et al. [6] found no differences between genders in the reduction (-30%) of the admissions for AMI compared to the control period, presenting an IRR of 0.70 (95% CI = 0.61-0.80) for men and 0.70 (0.56-0.88) for females. Moreover, no differences were observed by Solomon et al. [22] in Northern California between genders in the reduction of AMI admissions compared to the control period. Meanwhile, Moreno et al. in a study conducted in Madrid, Spain, found a significant reduction in males (-28.7%), but not in females during the pandemic compared with the pre-pandemic period [23].
The reduction in the admissions of females with STEMI in our study could be related to greater refutation and hesitation in seeking medical care during the COVID-19 pandemic. In our study, we observed a significant increase in the symptom onset to ICU admission in both genders compared to the control period, but there was a trend to a higher increase in female delay compared to males during the COVID-19 pandemic ( [15,16]. Females with STEMI are associated with significantly larger delays in seeking medical care related to psychosocial factors such as not disturbing, being a problem to others, and older age [13,14]. These factors probably worsened during the pandemic, especially due to the recommendations of self-isolation and physical distancing, impacting the admissions and the delay in hospital presentation and treatment. In our study, during the "normal" 2019 year, compared to males, females subjected to the so-called gender paradox of coronary disease tended to present later (424.72 ± 352.6 versus 467.46 ± 457.63), had worse outcomes, had higher mortality (6.0% versus 2.5%; p = 0.01), but tended to have smaller coronary disease extent (more than one-vessel CAD, less than two and three-vessel CAD) and better ejection fraction (50.68 ± 11.33 vs. 51.65 ± 12.40) ( Table 5). The paradox of coronary disease is described in other studies conducted worldwide [24] and previously in Albania [25].   Table 3.
As mentioned above, such an increase in male mortality leads to a reduction in differences between genders and losing "superiority" toward female patients regarding the ACS outcomes during the COVID-19 period. In our view, increased male mortality is related to a worse patient profile during the COVID-19 period as it is documented in previous studies for the overall ACS [11] and STEMI [12] mortality in Albania. The main male presentation during the study compared to the control period was STEMI (50.8% versus 39.5%; p = 0.007). The female presentation did not differ between periods. Male patients had a greater myocardial injury, as shown by the higher level of cTnI at presentation (21.01 ± 45.11 versus 9.01 ± 24.65; p = 0.0001) and lower LVEF (48.24 ± 11.68 versus 50.68 ± 11.33; p = 0.010) during the COVID-19 period. On the other hand, the level of cTnI and the LVEF were similar in female patients during both periods.
In our study, we found a reduction in ACS admissions and related invasive procedures in both males and females during the COVID-19 pandemic, mainly because of the reduction of UA (less severe) presentation in both genders. We found a reduction in female STEMI presentations, probably related to their specific psychological and social factors combined with pandemic factors. We documented a significant increase in male mortality, probably related to a greater proportion of STEMI patients, and greater myocardial damage (high cTnI and lower LVEF). The collateral damage of the pandemic, ACS not presented at all, or presented late, is extended in both genders, impacting future cardiovascular morbidity and mortality.

Strengths and limitations
The study included all consecutive patients, males and females, admitted with ACS in our center in two different periods, namely, pre-pandemic and pandemic (lockdown) periods, presenting the entire view of different gender admissions, management, invasive treatment, and complications. However, our study is a retrospective study and all data were taken from medical files with possible known biases [26].
As a reference center and the largest tertiary public center with primary PCI service, all ACS patients throughout Albania (regional hospitals) are normally transferred to our center. It is not clear the proportion of patients not transferred in Tirana and those treated in regional hospitals.
On the other hand, the patients diagnosed with COVID-19 and ACS were treated in another hospital and were not included in our study. To our knowledge, the number of patients with COVID-19 and ACS was small during the lockdown period, but the impact on admissions and in-hospital outcomes remains unknown.

Conclusions
Admissions for ACS were reduced similarly in males and females during the COVID-19 pandemic. Main reductions were observed in the UA group in both genders and STEMI predominantly in females, probably related to their specific psychological and social combined with pandemic factors. We identified a substantial increase in the overall ACS male mortality reducing the differences between genders. Further studies are necessary to better understand the increase in male mortality during this period.