Abstract
Background
Heart failure exhibits sex‐based differences in prevalence, clinical characteristics, and outcomes. However, these differences may have an interaction with age. This study investigates these disparities in Asian patients with acute heart failure according to age.
Methods and Results
We pooled data from the KorHF (Korea Heart Failure) and the KorAHF (Korean Acute Heart Failure) registries including 3200 patients between 2005 and 2009 and 5625 patients between 2011 and 2014, respectively, hospitalized for acute heart failure in Korea. Patients were categorized by their age into 2 groups: those with age ≥70 years and those with age <70 years. The primary endpoint was in‐hospital and postdischarge outcomes according to sex, stratified by age. Of 8825 patients, 45.7% had an age <70 years, and 54.3% had an age ≥70 years. Women were older on average in both groups. Differences in baseline characteristics were more apparent in the older group, with women having a higher prevalence of hypertension and valvular heart disease, whereas more men had chronic kidney disease, previous myocardial infarction, chronic obstructive pulmonary disease, and strokes. Both in‐hospital and postdischarge mortalities showed differences only in the older group, with men dying more (5.08% versus 7.41%, P<0.001; 17.95% versus 22.20%, P<0.001 respectively). This pattern persisted to adjusted analyses, which revealed that men have a 54% (odds ratio, 1.54 [95% CI, 1.17–2.04]) and 30% (hazard ratio, 1.30 [95% CI, 1.13–1.51]) increased in‐hospital and 1‐year mortality, respectively, compared with women.
Conclusions
In patients hospitalized with acute heart failure, male sex is an independent predictor of mortality in older patients but not younger patients.
Keywords: age, Asian, characteristics, heart failure, outcomes, sex difference
Subject Categories: Heart Failure
Clinical Perspective.
What Is New?
There was no difference in survival between men and women in all patients.
However, men >70 have higher in‐hospital and 1‐year postdischarge mortality rates than women; in contrast, sex seems to have a neutral effect on outcomes in those younger than 70 years old.
What Are the Clinical Implications?
These findings underscore the critical need for age‐adjusted strategies in the treatment and management of patients with heart failure, highlighting the nuanced interplay between age, sex, and health outcomes in this population.
Biological differences between men and women significantly affect disease presentation, progression, therapy response, and overall outcomes in various medical conditions. 1 Recognizing sex differences has prompted further investigation into their clinical implications in heart failure (HF). 2 Notably, HF with preserved ejection fraction predominantly affects women, whereas HF with reduced ejection fraction is more commonly diagnosed in men. 3 This distinction is potentially linked to sex‐specific differences in pathogenesis, pathophysiology, and other risk factors that merit further exploration. 4 Consequently, the clinical manifestations and responses to both pharmacological and nonpharmacological treatments vary between sexes. 5 , 6 In addition, the older age of female patients with HF compared with their male counterparts is clinically significant. Age is a well‐known influencer of therapy response and clinical outcomes across medical fields, presenting an important factor for special consideration in HF treatment. 7
Despite these insights, the prognostic value of sex in HF remains uncertain, with existing studies yielding conflicting results. 8 , 9 , 10 , 11 The potential interplay between sex and age in influencing clinical outcomes is particularly enigmatic and may partly explain the unexpected sex‐based findings in HF research. Therefore, more research is needed to elucidate how factors such as age may contribute to the sex‐based disparities that have previously been observed and perhaps provide a novel perspective on the multifactorial and heterogeneous pathophysiology of HF.
To bridge this critical gap in knowledge, we conducted a comprehensive analysis using data from 2 large prospective HF registries of 8825 patients hospitalized for acute HF in Korea. Our study aims to examine the independent prognostic impact of sex according to age in Asian patients with HF, providing a clearer understanding of these critical interplays in HF.
Methods
The data used in this study will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.
Study Design and Population
This study is a retrospective analysis of pooled data from 2 large, prospective HF registries in Korea—the KorHF (Korea Heart Failure) and the KorAHF (Korean Acute Heart Failure)—resulting in a combined registry of 8825 patients.
The KorHF Registry is a prospective multicenter registry designed to reflect the “real‐world” clinical data of Korean patients admitted for acute HF. It included 3200 consecutive patients hospitalized for acute HF from 24 tertiary centers between June 2004 and April 2009. HF was diagnosed according to the Framingham criteria. 12 The mean observational period was 1.7 years (range, 0.1–4.9 years). Details regarding the study design and result collection of both studies have previously been reported. 13 , 14 The KorAHF registry is a prospective, multicenter cohort study that consecutively enrolled 5625 patients hospitalized for acute HF syndrome from 10 well‐known tertiary university hospitals between March 2011 and December 2014. Detailed information on the study design and its results have been previously reported. 13 , 15 Patients with signs or symptoms of HF and either lung congestion, objective findings of left ventricular systolic dysfunction or structural heart disease were eligible for the study. All patients were scheduled for follow‐up at least 5 years after the index hospitalization. The mortality data for patients who were lost to follow‐up were collected from the National Insurance data or National Death Records.
The study protocol was approved by the institutional review board at each participating center, and all patients provided written informed consent before enrolment. This study protocol was conducted according to the principles of the Declaration of Helsinki.
Study Outcomes and Definitions
The primary outcomes were both in‐hospital and 1‐year postdischarge all‐cause death.
Based on age, patients were categorized into older (age ≥70 years) and younger age groups (age <70 years).
Statistical Analysis
Categorical variables were expressed as frequency and percentage proportion and compared using the χ2 test with no corrections incorporated. Continuous variables were expressed as mean±SD and compared using the t test.
For in‐hospital all‐cause death, a binary logistic regression analysis was performed with adjustment for significant covariates. For postdischarge death, we performed Kaplan–Meier survival analyses to compare the rate of all‐cause death events up to 1‐year follow‐up according to sex. A multivariable Cox proportional‐hazards regression model was then used to determine the effect size of sex as an independent predictor of all‐cause death. Out of the available variables (Table 1), we used variables that we believed to have clinical significance in determining patient prognosis. These included basic characteristics (age and sex), New York Heart Association class, relevant medical history directly or indirectly related to the cardiovascular system (hypertension, chronic obstructive pulmonary disease [COPD], diabetes, previous myocardial infarction [MI], previous valvular heart disease [VHD], and atrial fibrillation), markers of renal function (serum sodium level, serum urea nitrogen, and glomerular filtration rate), natriuretic peptides, type of HF, as well as discharge medications (renin‐angiotensin system inhibitors, beta blockers and mineralocorticoid receptor antagonist). Despite their clinical importance, variables such as CRP (C‐reactive protein), which had >10% missing values, or variables such as chronic kidney disease (CKD) and diastolic blood pressure with a strong correlation to other clinical variables according to variable inflation factors (glomerular filtration rate/serum urea nitrogen and systolic blood pressure respectively) were excluded to prevent multicollinearity in the multivariable models. Variables found to be statistically significant in the backward stepwise regression in the univariable analysis were included in the respective multivariable model. We compared the younger and older age groups in both primary outcomes.
Table 1.
Baseline Characteristics According to Sex and Age
| Age <70 y | Age ≥70 y | |||||
|---|---|---|---|---|---|---|
| Female sex | Male sex | P value | Female sex | Male sex | P value | |
| 1514 (37.6%) | 2516 (62.4%) | 2718 (56.7%) | 2077 (43.3%) | |||
| Age, y | 56.7±11.7 | 55.3±11.6 | <0.001 | 79.2±5.9 | 77.6±5.7 | <0.001 |
| De novo, % | 40.5% | 36.6% | 0.02 | 43.8% | 45.2% | 0.4 |
| Body mass index, kg/m2 | 23.6±4.3 | 24.2±4.0 | <0.001 | 22.7±3.9 | 22.7±3.3 | 0.9 |
| Past medical history | ||||||
| Hypertension, % | 39.8 | 43.0 | 0.051 | 67.0 | 63.0 | 0.004 |
| Diabetes, % | 29.7 | 31.3 | 0.3 | 34.8 | 37.5 | 0.053 |
| Chronic kidney disease, % | 10.2 | 11.1 | 0.4 | 10.9 | 17.9 | <0.001 |
| Atrial fibrillation, % | 26.1 | 26.6 | 0.7 | 34.3 | 32.8 | 0.3 |
| Previous myocardial infarction, % | 7.1 | 15.1 | <0.001 | 14.7 | 23.6 | <0.001 |
| Valvular heart disease, % | 18.7 | 9.9 | <0.001 | 16.4 | 12.9 | <0.001 |
| Chronic obstructive pulmonary disease, % | 4.0 | 6.8 | <0.001 | 7.8 | 15.1 | <0.001 |
| Cerebrovascular disease, % | 7.5 | 10.0 | 0.006 | 14.8 | 18.6 | <0.001 |
| New York Heart Association functional class, % | 0.6 | 0.01 | ||||
| II | 22.6 | 22.9 | 14.2 | 16.8 | ||
| III | 44.6 | 42.9 | 39.4 | 40.2 | ||
| IV | 32.8 | 34.2 | 46.5 | 43.0 | ||
| Physical exam | ||||||
| Systolic BP, mm Hg | 126.6±29.3 | 126.7±30.5 | 0.9 | 136.1±30.2 | 132.5±29.5 | <0.001 |
| Diastolic BP, mm Hg | 77.6±17.7 | 79.3±20.1 | 0.004 | 78.9±18.1 | 77.0±17.3 | <0.001 |
| Heart rate, beats/min | 92.5±25.4 | 92.7±25.6 | 0.8 | 92.6±26.0 | 90.6±25.7 | 0.009 |
| Laboratory findings | ||||||
| White blood cell, microL | 8434.9±4466.4 | 9273.7±4438.9 | <0.001 | 8916.9±4413.8 | 8690.7±4518.5 | 0.09 |
| Hemoglobin, mg/dL | 12.0±2.1 | 13.7±2.4 | <0.001 | 11.6±1.9 | 12.3±2.2 | <0.001 |
| Platelet, ×1000/microL | 228.0±88.4 | 217.6±84.9 | <0.001 | 224.5±88.2 | 199.5±91.9 | <0.001 |
| Serum sodium, mmol/L | 137.9±4.9 | 137.7±4.7 | 0.2 | 137.6±5.3 | 137.6±4.9 | 1.0 |
| Serum potassium, mmol/L | 4.3±0.7 | 4.4±0.7 | <0.001 | 4.3±0.7 | 4.4±0.7 | <0.001 |
| Serum urea nitrogen, mg/dL | 23.2±16.3 | 24.3±15.7 | 0.04 | 26.1±15.5 | 28.8±17.3 | <0.001 |
| Creatinine, mg/dL | 1.32±1.46 | 1.63±1.79 | <0.001 | 1.32±1.02 | 1.66±1.27 | <0.001 |
| GFR, mL/kg per 1.72m2 | 71.9±38.7 | 72.0±42.2 | 0.9 | 57.6±29.2 | 58.8±28.0 | 0.1 |
| GFR <60 mL/min per 1.72 m2 (%) | 38.9 | 35.5 | 0.03 | 59.1 | 53.8 | <0.001 |
| BNP, pg/mL | 1426.1±1332.4 | 1263.1±1544.6 | 0.04 | 1587.0±2323.2 | 1445.8±1956.5 | 0.2 |
| N‐terminal‐proBNP, pg/mL | 8924.4±11 558.4 | 6929.7±9263.6 | <0.001 | 10 334.1±10 589.7 | 9617.6±10 363.5 | 0.07 |
| C‐reactive protein, md/dL | 2.15±4.33 | 2.38±4.46 | 0.1 | 2.49±4.63 | 2.91±4.62 | 0.004 |
| Echocardiographic parameters | ||||||
| LV end‐diastolic diameter, mm | 55.8±9.6 | 61.2±10.5 | <0.001 | 53.5±9.2 | 58.1±9.2 | <0.001 |
| Left atrial diameter, mm | 46.9±10.5 | 48.3±9.6 | <0.001 | 47.4±9.7 | 48.1±9.7 | 0.03 |
| LV EF, % | 38.5±16.1 | 32.6±14.2 | <0.001 | 42.9±15.7 | 37.6±15.0 | <0.001 |
| E/e′ | 21.6±12.7 | 19.3±10.6 | <0.001 | 22.1±11.6 | 20.5±11.2 | <0.001 |
| HF types | <0.001 | <0.001 | ||||
| HF with reduced EF | 58.9% | 74.2% | 48.1% | 62.0% | ||
| HF with mildly reduced EF | 13.2% | 11.3% | 15.7% | 15.5% | ||
| HF with preserved EF | 27.9% | 14.5% | 36.2% | 22.4% | ||
| Medication at discharge | ||||||
| Renin‐angiotensin system‐inhibitor | 45.3% | 51.5% | <0.001 | 46.6% | 50.5% | 0.008 |
| Beta blockers | 37.7% | 44.4% | <0.001 | 38.2% | 37.2% | 0.5 |
| Mineralocorticoid receptor antagonist | 45.4% | 43.3% | 0.2 | 39.8% | 39.0% | 0.6 |
BNP indicates brain natriuretic peptide; BP, blood pressure; EF, ejection fraction; GFR, glomerular filtration rate; HF, heart failure; and LV, left ventricular.
A 2‐sided probability value <0.05 was considered indicative of a statistically significant difference. Statistical tests were performed using SPSS, V.22 (IBM, Armonk, NY, USA), R programming version 4.3.2. (The R Foundation for Statistical Computing, Vienna, Austria, http://www.R‐project.org).
Results
Patient Population
In the overall population, 4593 patients (52.0%) were male and 4232 (48.0%) were female (Figure 1 and Table S1); 4030 patients (45.7%) were <70 years and 4795 patients (54.3%) were ≥70 years. Notably, the younger age group consisted of more men, whereas women were more prevalent in the older age group (Table 1). On average, men were 5 years younger than women (71.1±13.7 versus 65.4±14.5 years, P<0.001). Comorbidities differed between sexes; women exhibited higher rates of hypertension (57.3% versus 52.0%, P<0.001), atrial fibrillation (31.4% versus 29.4%, P=0.041), and VHD (17.2% versus 11.3%, P<0.001). Conversely, men were more likely to have CKD (10.7% versus 14.1%, P<0.001), MI (12.0% versus 18.9%, P<0.001), COPD (6.4% versus 10.9%), and cerebrovascular disease (12.1% versus 13.9%, P<0.001).
Figure 1. Study population.
KorAHF indicates Korea Acute Heart Failure; and KorHF, Korea Heart Failure.
When stratified by age, in the young age group, men were more likely to have CKD, a history of cardio‐cerebrovascular disease and COPD, whereas women had a higher preponderance of hypertension and VHD. The older age group mirrored these trends, however, with an overall increase in the prevalence of these risk factors.
Echocardiographic analysis revealed that women generally exhibited higher left ventricular ejection fraction values compared with men (P<0.001 in both age groups), indicating notable sex differences in cardiac function.
In‐Hospital Mortality According to Sex and Age
Overall, 285 men (6.1%) and 291 women (5.1%) died before discharge (Table S2). When analyzed by age groups, mortality rates did not differ significantly in the younger age group (5.09% versus 5.05%, P=1.0). Nonetheless, in the older age group, men exhibited a higher mortality rate (5.08% versus 7.41%, P<0.001) (Table 2 and Figure 2A). A multivariable binary logistic regression analysis with adjustment for significant covariates showed that the male sex was associated with increased mortality only in the older age group (odds ratio [OR], 1.54 [95% CI, 1.17–2.04]; P=0.002). Interestingly, this association was not observed in the younger age group, indicating that sex‐based differences in mortality may become more pronounced with advancing age (Table 3).
Table 2.
Clinical Outcomes According Stratified by Age
| Female sex | Male sex | P value | |
|---|---|---|---|
| <70 y old | |||
| In‐hospital deaths, % | 5.09 | 5.05 | 1.0 |
| Postdischarge outcomes | |||
| 1‐y all‐cause death, % | 8.92 | 9.30 | 0.7 |
| 1‐y HHF, % | 19.37 | 17.88 | 0.2 |
| 1‐y death+HHF, % | 24.95 | 23.74 | 0.4 |
| ≥70 y old | |||
| In‐hospital deaths, % | 5.08 | 7.41 | <0.001 |
| Postdischarge outcomes | |||
| 1‐y all‐cause death, % | 17.95 | 22.20 | <0.001 |
| 1‐y HHF, % | 22.18 | 22.00 | 0.9 |
| 1‐y death+HHF, % | 35.09 | 37.34 | 0.1 |
HHF indicates hospitalization for heart failure.
Figure 2. Clinical outcomes.
A, In‐hospital mortality; B, 1‐y post‐discharge mortality; C, Composite of 1‐y ACM+HHF. ACM indicates all‐cause mortality; and HHF, hospitalization for heart failure.
Table 3.
Multivariate Analysis for In‐Hospital Mortality
| All patients | <70 y | ≥70 y | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Odds ratio | 95% CI | P value | Odds ratio | 95% CI | P value | Odds ratio | 95% CI | P value | |
| Male sex | 1.54 | 1.17–2.04 | 0.002 | ||||||
| Age | 1.00 | 0.99–1.01 | 0.6 | 0.99 | 0.97–1.00 | 0.1 | 1.02 | 0.99–1.04 | 0.1 |
| SBP | 0.98 | 0.98–0.99 | <0.001 | 0.98 | 0.98–0.99 | <0.001 | 0.98 | 0.98–0.99 | <0.001 |
| Diabetes | 0.51 | 0.29–0.85 | 0.01 | 1.21 | 0.91–1.60 | 0.2 | |||
| NYHA 3/4 | 1.58 | 1.12–2.29 | 0.01 | 1.45 | 0.83–2.72 | 0.2 | |||
| COPD | 1.50 | 1.06–2.07 | 0.02 | ||||||
| Previous MI | 1.24 | 0.93–1.66 | 0.1 | 1.58 | 0.84–2.91 | 0.1 | 1.23 | 0.89–1.68 | 0.2 |
| IHD | 1.51 | 1.18–1.94 | 0.001 | 1.68 | 0.97–2.84 | 0.06 | |||
| Na | 0.95 | 0.93–0.97 | <0.001 | 0.92 | 0.89–0.95 | <0.001 | 0.95 | 0.93–0.97 | <0.001 |
| SUN | 1.01 | 1.01–1.02 | <0.001 | 1.01 | 1.00–1.02 | 0.06 | 1.01 | 1.00–1.01 | 0.06 |
| GFR <60 | 1.56 | 1.11–2.21 | 0.01 | ||||||
| NP | 1.35 | 1.21–1.52 | <0.001 | 1.38 | 1.11–1.72 | 0.004 | 1.46 | 1.27–1.69 | <0.001 |
| Heart failure types | 1.32 | 0.99–1.72 | 0.048 | ||||||
| Age~sex interaction | 1.01 | 0.99–1.03 | 0.2 | ||||||
Logistic regression analysis with adjustment for sex, age, SBP, NYHA 3/4, hypertension, diabetes, COPD, previous MI, previous valvular heart disease, ECG atrial fibrillation, cause IHD, Na, SUN, GFR <60, NP for each quartile increase, E/e′. COPD indicates chronic obstructive pulmonary disease; GFR, glomerular filtration rate; IHD, ischemic heart disease; MI, myocardial infarction; Na, serum sodium level; NP, natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; and SUN, serum urea nitrogen.
Postdischarge Outcomes According to Sex and Age
Following hospital discharge, 1‐year mortality was observed in 649 men (15.1%) and 591 women (14.7%), with log‐rank P=0.8 (Figure 2B, Table S2). In the younger age group, there was no significant difference in 1‐year postdischarge mortality between men and women (8.92% versus 9.3%, log‐rank P=0.7). However, an absolute contrast was seen in the older age group where more male patients died (5.08% versus 7.41%; log‐rank P<0.001) (Table 2). In a multivariable Cox proportional‐hazards regression analysis with adjustment for significant covariates, the male sex conferred a 30% increased risk of 1‐year mortality (hazard ratio [HR], 1.30 [95% CI, 1.13–1.51]; P<0.001) in the older age group. In contrast, sex was not a significant predictor of 1‐year mortality in younger age groups (Table 4). Notably, there was a significant interaction between sex and age affecting postdischarge mortality in these patients (P=0.01).
Table 4.
Multivariate Analysis for 1‐Y Postdischarge All‐Cause Death
| All patients | <70 y | ≥70 y | |||||||
|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | HR | 95% CI | P value | |
| Male sex | 1.20 | 1.05–1.36 | 0.005 | 1.30 | 1.13–1.51 | <0.001 | |||
| Age | 1.04 | 1.03–1.05 | <0.001 | 1.03 | 1.02–1.05 | <0.001 | 1.05 | 1.03–1.06 | <0.001 |
| SBP | 0.99 | 0.99–0.99 | <0.001 | 0.99 | 0.98–0.99 | <0.001 | 0.99 | 0.99–1.00 | <0.001 |
| NYHA 3/4 | 1.30 | 1.07–1.58 | 0.009 | 1.53 | 1.19–1.96 | <0.001 | |||
| COPD | 1.40 | 1.18–1.68 | <0.001 | 1.36 | 0.92–2.01 | 0.1 | 1.47 | 1.21–1.79 | <0.001 |
| IHD | 1.13 | 1.00–1.28 | 0.06 | 1.14 | 0.99–1.32 | 0.07 | |||
| Na | 0.96 | 0.95–0.97 | <0.001 | 0.95 | 0.93–0.97 | <0.001 | 0.96 | 0.95–0.97 | <0.001 |
| SUN | 1.01 | 1.01–1.01 | <0.001 | 1.01 | 1.00–1.02 | 0.005 | 1.01 | 1.01–1.02 | <0.001 |
| NP | 1.35 | 1.27–1.43 | <0.001 | 1.39 | 1.24–1.57 | <0.001 | 1.33 | 1.24–1.43 | <0.001 |
| BB on discharge | 0.90 | 0.79–1.03 | 0.1 | ||||||
| RASi on discharge | 0.83 | 0.73–0.94 | 0.004 | 0.89 | 0.71–1.12 | 0.3 | 0.89 | 0.77–1.02 | 0.1 |
| MRA on discharge | 1.13 | 1.00–1.28 | 0.06 | 1.19 | 1.03–1.38 | 0.02 | |||
| Age~sex interaction | 1.01 | 1.00–1.03 | 0.01 | ||||||
Cox‐proportional hazards regression analysis with adjustment for sex, age, SBP, NYHA 3/4, hypertension, diabetes, COPD, previous myocardial infarction, previous valvular heart disease, ECG atrial fibrillation, IHD, Na, SUN, glomerular filtration rate <60, NP for each quartile increase, RASi on discharge, BB on discharge, MRA on discharge, HF types where HF with reduced EF=1 HF with mildly reduced EF=2 HF with preserved EF=3. BB indicates beta blocker; COPD, chronic obstructive pulmonary disease; EF, ejection fraction; HF, heart failure; HR, hazard ratio; IHD, ischemic heart disease; MRA, mineralocorticoid receptor antagonist; Na, serum sodium level; NP, natriuretic peptide; NYHA, New York Heart Association; RASi, renin‐angiotensin system inhibitor; and SBP, systolic blood pressure; and SUN, serum urea nitrogen.
Temporal Variation
As we pooled 2 registries from different time periods (KorHF, 2004–2009; KorAHF, 2011–2014), we performed a sensitivity analysis to account for the temporal variation in our study population by including the “registry period” as a covariate in both of our multivariable models. Though the registry period was associated with mortality, the overall interaction between sex and mortality upon subgroup analysis was similar (Tables S3 and S4).
Discussion
This study examined sex‐based disparities by age in Asian patients hospitalized for acute HF using data from 8825 Asian patients across 2 large Korean registries. Women were found to be generally older and exhibited a higher prevalence of hypertension and VHD, whereas men had more previous MI, CKD, and COPD, among others. There was no difference in survival between men and women in all patients. However, age‐stratified analyses revealed that men ≥70 experienced in‐hospital and postdischarge mortality that were 54% and 30% higher, respectively, than those of women. In contrast, sex seems to have a neutral effect on these outcomes in those younger than 70 years old. These findings suggest that a sex‐dependent disparity in mortality was influenced by age, affecting both in‐hospital and postdischarge outcomes in patients with HF.
Baseline Characteristics Across Age Groups
When comparing trends between the sexes, female patients were older than their male counterparts and had higher left ventricular ejection fraction, whereas male patients more frequently presented with CKD, COPD, and a pronounced history of ischemic heart disease and strokes. These trends align with regional and global registries, 8 , 9 , 16 , 17 except for the Swedish HF registry, 16 where women exhibited higher COPD rates, possibly due to different smoking patterns. 18 , 19 Notably, the distribution of risk factors was consistent across age groups; however, there are 2 crucial observations. Firstly, despite the same trend, the older age group had a higher proportion of patients with risk factors, indicating a more clinically significant impact (Figure 3). 20 Secondly, there was a notable reversal in hypertension prevalence between sexes across the age groups, potentially reflecting an accelerated development of hypertension in women after losing estrogen‐led protection. 21 Overall, despite women being older, men exhibited more unfavorable baseline characteristics across both age groups, with these differences becoming more pronounced in the older age group.
Figure 3. Distribution of risk factors of postdischarge death according to sex stratified by age.
AF indicates atrial fibrillation; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; MI, myocardial infarction; and VHD, valvular heart disease.
Though sex‐based trends in numerous variables, including age, comorbidities, and echocardiographic data (left ventricular ejection fraction), were largely shared globally among registries from Korea, Spain, Sweden, and Japan, it was observed that the absolute values of some variables were not as comparable. Most prominently, the mean age of our study population (65.4 years for men; 71.1 years for women) was lower than other registries. This observation was previously reported in a comparison with ADHERE (Acute Decompensated Heart Failure National Registry), ATTEND (Acute Decompensated Heart Failure Syndromes), and OPTIMIZE‐HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure) registries by our group. 22 Perhaps as a function of the age difference, the prevalence of comorbidities such as hypertension, diabetes, and atrial fibrillation was lower in our study as well; however, once we stratified our patients by age, the older subgroup exhibited similar values to other registries.
In‐Hospital Mortality
A principal finding of this study is that sex emerged as a significant predictor of in‐hospital mortality in the older age group, whereas it had an insignificant effect in the younger age group. The relationship between sex and in‐hospital mortality in HF patients remains controversial, with many studies indicating no meaningful interaction. 17 , 23 , 24
In the younger age group, predictors of in‐hospital mortality included age, systolic blood pressure, diabetes, New York Heart Association class, previous MI, ischemic heart disease, low sodium levels, high serum urea nitrogen, elevated natriuretic peptide levels, and HF type, but not sex. Conversely, in the older age group, sex emerged as a significant predictor. We speculate that the observed divergence in mortality rates may be explained by the differing accumulation of comorbidities, such as previous MI, across age and sex groups. This observation underscores the importance of considering age‐specific differences in mortality studies, which may otherwise be obscured when analyzing the overall population.
Postdischarge Mortality
Results for postdischarge outcomes mirrored those of in‐hospital mortality, identifying male sex as a predictor of mortality in the older age group only. Despite conflicting findings in current research on overall postdischarge mortality, there is a more consistent indication of a female survival advantage. 8 , 9 , 17 Notably, the Kyoto Congestive Heart Failure registry showed a significantly lower risk of 1‐year postdischarge all‐cause death in women, attributing this to potential cardioprotective mechanisms associated with remodelling and neurohormonal activation. 9 , 25
The exact reason for the differential impact of sex on mortality by age remains unclear. Given the higher average age of female patients, it is plausible they develop HF later than male patients. As both sexes age, the accumulation of comorbidities such as ischemic heart disease, COPD, and CKD, which may affect men and women differently, becomes more pronounced. 20 The typically younger age of men might offset these risk factors. 26 Further age‐based analysis is warranted to illuminate these nuanced differences.
Limitations
This study has several limitations. Firstly, due to the retrospective nature of our study, we cannot establish causality; we can only identify associations. Therefore, our study results serve as a basis for generating hypotheses. This registry approach also makes our results susceptible to biases such as omitted variable bias—which disallowed us from accounting for clinically significant variables such as CRP and demographic variables in our multivariable models—as well as sampling and healthy volunteer biases. However, the main strength of this study lies in it being the largest prospective HF registry with meticulous data collection, lending considerable reliability to the findings. Secondly, due to the inclusion of registries from different years, temporal bias is introduced, with variations in patient characteristics and HF therapy that might influence the findings. Though this difference in time periods reduced the chances of overlapping patients in the 2 registries, we cannot definitively exclude that possibility either. Thirdly, the study's earlier recruitment period precluded the use of novel HF medications like sacubitril/valsartan or sodium glucose cotransporter‐2 inhibitors, leaving open the question of how contemporary treatment modalities might affect the sex‐differential effects on mortality. Lastly, our study population, on average, appears to be younger and have a lower prevalence of comorbidities than certain registries around the world. Despite our attempt to control for these differences in our multivariable analyses, they may be reflecting a more fundamental variance in health care—especially when comparing to intercontinental registries—and limit the generalizability of our study.
Conclusions
This study, using large prospective HF registry data, establishes the male sex as an independent predictor of mortality in older, but not younger, Asian patients hospitalized with acute HF. These findings underscore the critical need for age‐adjusted strategies in the treatment and management of patients with HF, highlighting the nuanced interplay between age, sex, and health outcomes in this population.
Sources of Funding
This work was supported by Research of Korea Centers for Disease Control and Prevention (2010‐E63003‐00, 2011‐E63002‐00, 2012‐E63005‐00, 2013‐E63003‐00, 2013‐E63003‐01, 2013‐E63003‐02, and 2016‐ER6303‐00) and by the SNUBH Research Fund (Grant no 18‐2023‐0011).
Disclosures
None.
Supporting information
Tables S1–S4
Acknowledgments
KorHF and KorAHF Investigators (in alphabetical order): Youngkeun Ahn, Sang Hong Baek, Shung Chull Chae, Myeong‐Chan Cho, Hyun‐Jai Cho, Dong‐Ju Choi, Seok‐Min Kang, Hyung Seop Kim, Jae‐Joong Kim, Yung‐Jo Kim, Hae‐Young Lee, Byung‐Hee Oh, Kyu‐Hyung Ryu, In‐Whan Seong, Mi‐Seung Shin, Eun‐Seok Jeon, Seongwoo Han, Myung‐Mook Lee, Byung‐Su Yoo.
This article was sent to Mahasin S. Mujahid, PhD, MS, FAHA, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.124.034419
For Sources of Funding and Disclosures, see page 9.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Tables S1–S4