Sex differences in treatment and outcomes of patients with in‐hospital ST‐elevation myocardial infarction

Abstract Background and Hypothesis Two cohorts face high mortality after ST‐elevation myocardial infarction (STEMI): females and patients with in‐hospital STEMI. The aim of this study was to evaluate sex differences in ischemic times and outcomes of in‐hospital STEMI patients. Methods Consecutive STEMI patients treated with percutaneous coronary intervention (PCI) were prospectively recruited from 30 hospitals into the Victorian Cardiac Outcomes Registry (2013−2018). Sex discrepancies within in‐hospital STEMIs were compared with out‐of‐hospital STEMIs. The primary endpoint was 12‐month all‐cause mortality. Secondary endpoints included symptom‐to‐device (STD) time and 30‐day major adverse cardiovascular events (MACE). To investigate the relationship between sex and 12‐month mortality for in‐hospital versus out‐of‐hospital STEMIs, an interaction analysis was included in the multivariable models. Results A total of 7493 STEMI patients underwent PCI of which 494 (6.6%) occurred in‐hospital. In‐hospital versus out‐of‐hospital STEMIs comprised 31.9% and 19.9% females, respectively. Female in‐hospital STEMIs were older (69.5 vs. 65.9 years, p = .003) with longer adjusted geometric mean STD times (104.6 vs. 94.3 min, p < .001) than men. Female versus male in‐hospital STEMIs had no difference in 12‐month mortality (27.1% vs. 20.3%, p = .92) and MACE (22.8% vs. 19.3%, p = .87). Female sex was not independently associated with 12‐month mortality for in‐hospital STEMIs which was consistent across the STEMI cohort (OR: 1.26, 95% CI: 0.94–1.70, p = .13). Conclusions In‐hospital STEMIs are more frequent in females relative to out‐of‐hospital STEMIs. Despite already being under medical care, females with in‐hospital STEMIs experienced a 10‐min mean excess in STD time compared with males, after adjustment for confounders. Adjusted 12‐month mortality and MACE were similar to males.


| INTRODUCTION
Coronary artery disease is the leading cause of death worldwide. 1 Despite advancements in medical therapy and device technology, patients with ST-elevation myocardial infarction (STEMI) continue to suffer from high mortality. 2 Rapid reperfusion is key in the treatment of STEMI with time from symptom onset to revascularization closely linked to outcomes. [3][4][5][6] Two groups of patients with STEMI who demonstrate a particularly poor prognosis are females [7][8][9][10][11][12] and patients with so-called "in-hospital STEMI," that is, STEMI that happens while the patient is already admitted to the hospital. [13][14][15] With regard to females, factors associated with poorer outcomes include significantly longer ischemic times in females compared with males [16][17][18] as well as more bleeding 19 and less guideline-directed medical therapy. 20,21 Similarly, patients with in-hospital STEMI have been found to have longer ischemic times compared with patients presenting with out-of-hospital STEMI. 13,22 Further, both female patients, and those with in-hospital STEMI, are older and have more comorbidities. They are both less likely to undergo invasive diagnostic management as well as to be treated with percutaneous coronary intervention (PCI). 15,20,23,24 Despite these concerning data, patients with in-hospital STEMI have been under-researched, with less than a handful of studies conducted. The topic is of critical importance during the current coronavirus-19 pandemic: Acute cardiac injury is present in 17% of patients with COVID-19 25 and is predictive of in-hospital mortality in this patient group. 25 Importantly, STEMIs do occur both as the first sign of COVID-19 or in-hospital patients admitted for COVID- 19. 26 In particular, no research has been undertaken with regard to female patients with in-hospital STEMI and possible sex disparities in this patient group and as compared with overall STEMI cohorts. The aim of this study was to evaluate sex differences in ischemic times and outcomes of patients with in-hospital STEMI in a large, multicenter, prospective registry. where symptom onset occurred before presentation to hospital. For the analysis of symptom-to-device (STD) time, the following patients were excluded from the analysis: (i) patients without a recorded time of symptom onset, (ii) patients who presented for PCI more than 12 h after symptom onset, (iii) patients who had symptom onset while admitted in a non-PCI capable hospital (for the in-hospital STEMI), and (iv) patients who presented to a non-PCI capable hospital (for the out-of-hospital STEMI, outlined in Figure 1).

| METHODS
Sex discrepancies in in-hospital STEMI patients were analyzed and compared with sex discrepancies in out-of-hospital STEMI patients for the primary endpoint of 12-month all-cause mortality. Accordingly, to assess for sex discrepancies in reperfusion delays, the percentage of male and female in-hospital STEMI patients achieving an STD time ≤90 min was analyzed. 6 Preprocedural creatinine was collected up to 60 days before the PCI and the Cockcroft−Gault formula used to determine the esti- To investigate the relationship between sex and 12-month mortality outcomes for out-of-hospital STEMI patients compared with in-hospital STEMI patients, interaction was utilized.
A p value <.05 was considered statistically significant for all analyses. Statistical analyses were performed using Stata version 14.

| RESULTS
A total of 7493 patients underwent PCI for the treatment of STEMI of which 494 (6.6%) were in-hospital STEMI. Of these, 158 patients (31.9%) were female compared with 1394 female patients (19.9%) in the out-of-hospital STEMI group (outlined in Figure 1). Table 1 shows the baseline demographic and clinical characteristics. Females with in-hospital STEMI were significantly older (69.5 vs. 65.9 years, p = .003) than males but there were no differences in comorbidities and treatment with anticoagulants.
Female and male in-hospital STEMI patients had similar rates of stent thrombosis (17.1% vs. 16.4%). Female in-hospital STEMI patients were significantly less likely to receive statins (p = .030) and P2Y12 inhibitors (p = .040, presented in Table 2 Figure 2). 4 Table S1). However, the differences were not statistically significant. In the multivariable models, including the interaction analysis for sex impact, there was no relationship between sex and in-hospital symptom onset for 12-month mortality (shown in

| DISCUSSION
This is the first study to assess sex differences in patients with an inhospital STEMI, utilizing a large registry that captured all STEMI patients who were treated with PCI. The main findings of our study were that: (i) women comprised a larger proportion of patients with in-hospital STEMI compared with out-of-hospital STEMI; (ii) women with in-hospital STEMI had significantly longer adjusted ischemic times compared with men and received significantly less Ticagrelor and statins; (iii) there was no significant interaction between sex and in-hospital symptom onset for 12-month and 30-day mortality, MACE, MACCE, and major bleeding and (iv) female sex was not independently associated with higher 12-month mortality for inhospital STEMI patients.
Two groups of patients with STEMI are known to be distinct in their characteristics: women and patients with in-hospital STEMI. Both groups have been described to suffer worse outcomes after a STEMI. 12,15,18 However, data on in-hospital STEMI are scant and no previous studies have addressed sex differences in this unique cohort. This is surprising given that patients who are hospitalized for a noncardiac cause have a 40−50 times higher likelihood of suffering a STEMI compared with people in the community. 30,31 In our cohort, 6.6% of all STEMI cases occurred in patients already admitted to the hospital, consistent with the 5%−8% described in previous literature. 15,22,32 Of interest, women made up a larger proportion (31.9% vs. 19.9%) of patients with in-hospital STEMI, compared with standard out-of-hospital STEMI. As a result, identifying sex differences is important.
Interestingly, sex discrepancies in baseline characteristics were not as evident in patients with in-hospital STEMI compared with outof-hospital STEMI patients. Equally so, peri-procedural characteristics were not significantly different between men and women with inhospital STEMI, which is unlike the sex difference observed in patients with out-of-hospital STEMIs.
Female in-hospital STEMI patients had higher absolute rates of MACE, MACCE, all-cause mortality, and major bleeding; however, they did not reach statistical significance, likely due to the small sample size. The significant sex difference identified for female patients with in-hospital STEMI was a mean 10-min delay from symptom onset to reperfusion when compared with males. Importantly, this difference was evident even after adjustment for confounders. Significantly longer ischemic times in females compared with males in the general STEMI cohort are well described, largely driven by delays in symptom T A B L E 1 Baseline characteristics according to sex and in-hospital versus out-of-hospital STEMI onset to FMC or hospital arrival. [16][17][18]33,34 In our inpatient STEMI cohort, significant sex delays were seen, despite patients being already admitted to the hospital. However, similar factors may be at play. Females experience a higher rate of associated symptoms and therefore healthcare providers are less likely to attribute their chest pain to a STEMI compared with males. 18,34,35 The potential for both patient and professional bias is also possible, with a lower perception of females' risk for MI. 16  Raising awareness of sex differences in this under-studied population of patients with in-hospital STEMI is required to improve outcomes and further narrow the gap.

ACKNOWLEDGMENT
Funding for this study was provided by the Epworth Medical Foundation.