Sex Disparity in the In-Hospital Outcomes of Patients with Kidney Disease Admitted for Myocardial Infarction: Insights from a Large National Database

Based on the American Heart Association (AHA) Heart Disease and Stroke Statistics 2023 Update, coronary heart disease (CHD) remains the number one cause of death in the USA in 2020 [1]. Moreover, every 40 s, an American suffers myocardial infarction (MI), the most common form of CHD [2]. In a previous analysis on sex differences in in-hospital outcomes following admission for acute coronary syndrome, it was observed that females had a higher mortality and were less likely to undergo coronary angiography and percutaneous coronary intervention (PCI) when compared with their male counterparts [3]. In addition, a pooled analysis of 56 studies revealed that females who were hospitalized for ST-segment elevation myocardial infarction (STEMI) were more likely to experience major bleeding stroke and repeat MI [4]. Regardless of the stage of chronic kidney disease (CKD), CHD remains the leading cause of morbidity and mortality in patients with kidney disease. A study by Ismail et al. [5] found that patients with STEMI and CKD were more likely to develop vascular complications, major adverse cardiovascular event, and in-hospital death when compared to those with normal renal function. Moreover, a Swedish study in 2011, which evaluated the association of sex with renal insufficiency in patients with STEMI, showed a considerable difference in the prevalence of kidney disease in STEMI between males and females, and kidney disease seemed to be a more important prognostic marker in women [6]. This study aims to determine the impact of sex differences in in-hospital outcomes among patients who were admitted for ST-segment elevation with concomitant CKD or end-stage renal disease (ESRD).

This analysis was performed using the National Inpatient Sample database. This database is published yearly by the Healthcare Cost and Utilization Project and contains information regarding patient discharges and outcomes across the country. The National Inpatient Sample comprises data representing 20% of all hospital admissions in the USA and contains data on over 7 million hospitalizations annually. It is continually referenced and used to identify yearly trends and patterns for various clinical topics. This publicly available database does not contain patients’ names or any other personal identifiers.

We used the International Classification of Diseases, Ninth and Tenth Revision (ICD-9 and -10) codes (online suppl. Table S1; for all online suppl. material, see https://doi.org/10.1159/000540783) to identify hospitalizations from STEMI in our study period. These codes were also used in other studies by Liu et al. [7] and Freisinger et al. [8], which also reported sex disparities in MI. These patients with STEMI were then stratified as to having CKD versus ESRD. Records with missing data were excluded. The primary outcome of interest was in-hospital mortality. Secondary outcomes evaluated included ischemic stroke, major bleeding complications, pressor requirement, permanent pacemaker (PPM) implantation, percutaneous coronary intervention, coronary artery bypass grafting (CABG), surgery, pericardiocentesis, mechanical circulatory support (MCS), and mechanical ventilation. Baseline patient characteristics included demographics (age and sex), primary expected payer, hospital characteristics (teaching vs. non-teaching, bed size; small, medium, and large), hospital region (Northeast, Midwest, South, and West), and Charlson Comorbidity Index as defined by the Agency for Healthcare Research and Quality.

STATA version 17.0 (Stata Corp, TX, USA) was used to conduct all analyses. Continuous variables were analyzed using the independent Student’s t test, while the Fisher’s exact test was used for proportional variables. Binary or dichotomous or categorical variables were analyzed using logistic regression. Clinical relationships were determined using logistic regression when analyzing discrete variables with unequal and variable distributions. Linear regression was used when analyzing relationships for continuous variables. A univariate logistic regression and linear regression model analysis were used for the unadjusted outcomes measured. A univariate model was used to calculate unadjusted odds ratios for the primary and secondary outcomes. In contrast, a multivariable logistic and linear model was used to calculate adjusted odds ratios (aORs) for the primary and secondary outcomes. Variables with p values <0.1 within our univariate model were added to our multivariable logistic regression model. All p values were two sided, with a value of <0.05 considered as statistically significant in the multivariable analysis model. Charlson Comorbidity Index was used to adjust for comorbidity burden for the primary and secondary outcomes and to quantify the severity of comorbidities. Our model adjusted for confounding covariates with age, gender, insurance, hospital characteristics (region, bed size, and teaching status), nicotine use, comorbidities, baseline oxygen use, and Charlson Comorbidity Index.

Patients with STEMI were stratified based on their renal function: without CKD, with CKD, and with ESRD. A total of 1,283,255 STEMI without CKD patients, 158,715 STEMI with CKD patients, and 22,690 STEMI with ESRD patients were identified (Fig. 1). Males comprised the majority in all cohorts (1,005,265 [68.6%] males vs. 459,395 [31.4%] females). In the STEMI with CKD cohort, females were noted to be older than males (75.9 ± 0.12 vs. 70.4 ± 0.09, p ≤ 0.0001). More females had a history of hypertension (37.1% vs. 33.9%, p < 0.001), diabetes (51.9% vs. 49.6%, p < 0.001), congestive heart failure (50.7% vs. 43.1%, p < 0.001), hypothyroidism (22.3% vs. 9.6%, p < 0.001), chronic obstructive pulmonary disease (12.4% vs. 11.5%, p < 0.001), peripheral vascular disease (14.7% vs. 13.5%, p < 0.001), carotid artery disease (2.5% vs. 2.1%, p < 0.001), obesity (19.4% vs. 17.8%, p < 0.001), anemia (39.5% vs. 29.1%, p < 0.001), valvular disease (18.2% vs. 12.2%, p < 0.001), fluid and electrolyte disorders (40.9% vs. 35.9%, p < 0.001), and prior stroke (13.7% vs. 11.3%, p < 0.001). Meanwhile, more males had smoking history (27.0% vs. 18.7%, p < 0.001), PCI (6.9% vs. 5.4%, p < 0.001), CABG (12.7% vs. 10.1%, p < 0.001), and liver disease (7.1% vs. 6.2%, p < 0.001) (Table 1).

In the STEMI with ESRD cohort, females were noted to be older than males (67.0 ± 0.29 vs. 65.3 ± 0.24, p < 0.001). Females have more history of diabetes (72.4% vs. 64.6%, p < 0.001), hypothyroidism (17.0% vs. 8.7%, p < 0.001), obesity (17.6% vs. 1.9%, p < 0.001), anemia (67.1% vs. 62.9%, p < 0.001), valvular disease (17.3% vs. 14.5%, p = 0.01), and prior stroke (15.3% vs. 12.9%, p = 0.02). Meanwhile, more males had smoking history (22.8% vs. 14.7%, p < 0.001) (Table 1).

Among patients with STEMI and CKD, a higher rate of in-hospital mortality was seen in females compared to their male counterparts (16.7% vs. 12.7%, aOR = 1.13, 95% CI: 1.05–1.21, p < 0.001). There was a significant increase in the trend STEMI hospitalizations among patients with CKD (Fig. 2) and ESRD (Fig. 3). Although the hospitalization trend increased, there was no increase in mortality from 2012 to 2020 (Fig. 4). Females were more likely to develop ischemic stroke (4.0% vs. 3.0%, aOR = 1.16, 95% CI: 1.01–1.34, p = 0.04). Females were also less likely to receive vasopressors (3.1% vs. 3.8%, aOR = 0.77, 95% CI: 0.67–0.88, p < 0.001), PCI (58.8% vs. 67.6%, aOR = 0.88, 95% CI: 0.84–0.93, p < 0.001), CABG (4.7% vs. 8.1%, aOR = 0.49, 95% CI: 0.44–0.55, p < 0.001), MCS (9.9% vs. 14.5%, aOR = 0.62, 95% CI: 0.57–0.67, p < 0.001), and mechanical ventilation (14.3% vs. 16.4%, aOR = 0.80, 95% CI: 0.74–0.86, p < 0.001). There was no sex difference in the odds of major bleeding, PPM implantation, surgery, and pericardiocentesis (Table 2).

Among patients with STEMI and ESRD, we found no significant difference in mortality between males and females (22.5% males vs. 242.2% females, aOR = 1.06, 95% CI: 0.92–1.23, p = 0.42), but females were less likely to develop acute kidney injury (16.2% vs. 21%, aOR = 0.77, 95% CI: 0.64–0.91, p < 0.001). In addition, females were also less likely to undergo CABG (5.0% vs. 8.7%, aOR = 0.54, 95% CI: 0.42–0.70, p < 0.001) and MCS (12.8% vs. 17.8%, aOR = 0.69, 95% CI: 0.58–0.83, p < 0.001). There was no sex difference in the odds of major bleeding, use of vasopressors, PPM implantation, PCI, surgery, pericardiocentesis, ischemic stroke, nor mechanical ventilation (Table 2).

The most important findings of our study can be summarized as follows: (1) Female patients with STEMI and CKD were less likely to get revascularization in the form of PCI or CABG, were less likely to receive vasopressors and MCS, were more likely to develop ischemic stroke, and demonstrated higher in-hospital mortality. (2) There was no sex difference in the in-hospital mortality among patients with STEMI and ESRD. (3) Female patients with STEMI and ESRD were less likely to receive CABG and MCS. Multiple studies on gender disparities in the outcomes of patients with STEMI without CKD has shown higher mortality among females compared to male counterparts [9‒13]. The higher rate of early death among female patients with STEMI may be due to several confounding variables seen in the baseline cardiovascular risk factors and clinical profiles of females compared to male patients [9, 10]. Higher prevalence of hypertension, diabetes, heart failure, and obesity was also noted among females compared to their male counterparts. Therefore, the poor cardiovascular risk profiles among women with STEMI may play a role in the sex differences observed in mortality [9‒13]. Besides differences in baseline clinical profiles, suboptimal healthcare utilization among females compared with males presenting with STEMI has also been identified as a contributory factor for a higher mortality rate in the former [13‒15]. Several studies have also demonstrated a less aggressive approach in managing cardiovascular diseases in females compared to males [16‒18]. Moreover, female patients are also more likely to have a prehospital missed diagnosis of STEMI and a higher incidence of presentation to a non-PCI-capable facility [19]. Although the causes of these discrepancies are unclear, they are likely to contribute to the increased in-hospital mortality observed among female patients with STEMI without CKD [10].

There is a significant sex disparity in outcomes among STEMI patients with CKD. As previously mentioned, recent studies observed that varied baseline characteristics indicate a less favorable risk profile among females compared to males in cases of acute MI [6, 20, 21]. In particular, one of the important factors that affect the treatment success, morbidity, and mortality of STEMI is the concomitant diagnosis of CKD. Although STEMI alone poses a great health burden, the result of this study confirms the strong prognostic impact of CKD in in-hospital outcomes. CKD is linked to various metabolic irregularities, including oxidative stress, insulin resistance, lipid imbalances, and inflammation. A number of studies have reported that female sex and CKD have independent associations specifically among STEMI patients while some demonstrate a higher calculated mortality risk and negative prognostic significance in males [22]. This potential cause of differences in reported mortality risk was explored in a population-based cross-sectional study by Lin et al. [23] in 2021. They showed an overall higher CKD prevalence among females but lower CKD awareness. Females having longer life expectancy compared to males and possible underestimation of kidney function with inappropriate use of estimated glomerular function rate equations were mentioned as some of the potential reasons for higher CKD prevalence in the former population [23]. Furthermore, an accelerated decline in kidney function in males could be attributed to poor lifestyles or the lack of protective effects of estrogen. However, this study also reported that the male to female ratio of CKD prevalence increases from stage 3 to 5 and in ESRD [23].

We established stroke was more common among females with CKD who were admitted for STEMI. In a study by Savic et al. [24], female patients with STEMI who were treated with PCI had a higher incidence of post-MI ischemic stroke during hospitalizations. In a Taiwanese population, female MI patients were found to have higher risk of stroke from hospitalization until follow-up after 3 years [25]. Moreover, factors such as prior ischemic stroke, STEMI, atrial fibrillation, and heart failure during hospitalization are predictors of an increased risk of in hospital ischemic stroke [26]. CKD itself is a predictor of stroke among patients undergoing PCI for STEMI [27]. Moreover, old age, hypertension, and diabetes mellitus also play a significant role in the occurrence of thrombotic events following MI [28].

Similar to patients with CKD, female patients with ESRD were also less likely to undergo CABG. Impaired renal function is the primary contributory factor in the lower likelihood of receiving these invasive interventions and revascularization procedures [29, 30]. In fact, a study by Pang et al. [31] on patients with ESRD who underwent isolated CABG between 2006 and 2015 reported that CABG is associated with high operative mortality and poor long-term survival in these patients. Operative mortality occurred in 13.4% patients in this study and the median survival was 4.3 years [31]. Multivariable analysis has determined that preoperative left ventricular ejection fraction and non-elective status of operation are predictors of operative mortality [31]. In addition, females are likely to have more significant comorbidity burden and less favorable anatomy for coronary artery bypass compared to men because of narrower vessels [32]. Women are also less likely to receive cardiac catheterization or revascularization overall, leading to the under-recognition and treatment of women with CVD [32].

We established that among patients with STEMI with concomitant ESRD, females were less likely to undergo MCS. Overall, women are less likely to undergo invasive cardiac procedures, including MCS [33]. Among patients with familial hypercholesterolemia admitted for AMI, women are also significantly less likely to receive MCS compared to men [34]. In-hospital outcomes for patients with ESRD who develop acute coronary syndrome and are treated with combined PCI and MCS experience significantly worse outcomes [35]. This is in line with the data from the European Registry for patients with MCS cohort that reported less likelihood for women to be referred for MCS as they often present with unstable conditions and advanced critical heart failure state [35]. This variance in management may be explained by sex-related discrepancies in STEMI presentation and co-morbidity profile in women, leading to misdiagnosis and delayed revascularization and other cardiac interventions [35]. Women have been found to be more likely to develop heart failure and cardiogenic shock during MI hospitalization despite less extensive coronary artery disease and smaller infarct size, suggesting a significant disparity in optimal management between the two sexes [35].

Increased in-hospital mortality rates were shown for females admitted for STEMI with CKD. However, for STEMI patients with ERD, there was no significant difference between males and females with respect to mortality rates. Further research needs to be conducted to better explain this said difference in outcomes.

Ethics approval for this paper is not required because this study is based exclusively on published literature. Patient consent was not needed as this study was based on publicly available data.

Edgar V. Lerma, MD: advisory board/speaker bureau: AstraZeneca, Calliditas, GSK, Novartis, Otsuka, Travere, and Vifor. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

This work was not funded.

Frederick B. Rivera, MD: conceptualization, data curation, formal analysis, investigation, methodology, validation, writing – original draft, and writing – review and editing; Frederick B. Rivera, MD, Jade Monica Marie J. Ruyeras, MD, John Andrew C. Amigo, Marie Francesca M. Ansay, and Maria Angela Matabang, MD: writing – original draft and writing – review and editing; Wailea Faye C Salva, MD, and Samantha Tang, MD: data curation and writing – original draft; John Andrew C. Amigo, Marie Francesca M. Ansay, Maria Angela Matabang, MD, Jeremiahdominic T. Balbin, MD, Polyn Luz S. Pine, MD, MBA, Gabriel A. Tangco, MD, MBA, John Andrew C. Amigo, Marie Francesca M. Ansay, Maria Angela Matabang, MD, and Nathan Ross B. Bantayan, BSc: writing – original draft; and Edgar V. Lerma, MD, Fareed Moses S. Collado, MD, Kenneth Ong, MD, and Amir Kazory, MD: writing – review and editing.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.