Abstract
Aims
Sex differences in long‐term post‐discharge clinical outcomes in Asian patients hospitalized for acute decompensated heart failure (HF) persist despite the world‐wide implementation of guideline‐directed medical therapy for decades. The present study aims to elucidate the puzzling dilemma and to depict the directions of solution.
Methods and results
Between 2011 and 2020, a total of 12 428 patients (6518 men and 5910 women, mean age 73.50 ± 14.85) hospitalized for acute decompensated HF were retrospectively enrolled from a university HF cohort. Compared with men, women hospitalized for acute decompensated HF were older in age (76.40 ± 13.43 vs. 71.20 ± 15.67 years old, P < 0.0001) with more coexisting hypertension, diabetes, hyperlipidaemia and moderate to severe chronic kidney disease, but less with ischaemic heart disease, cerebrovascular disease and chronic obstructive pulmonary disease (P < 0.0001). In echocardiography measurement parameters, women had smaller left ventricular and left atrial dimensions, higher left ventricular mass index, higher left ventricular ejection fraction (LVEF) and more in HF with preserved ejection fraction (EF) category (LVEF > 50%) than men (P < 0.0001). In HF therapy, women compared with men received more guideline‐directed medical HF therapies including angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor–neprilysin inhibitors and sodium–glucose cotransporter‐2 inhibitors, but similar beta‐blockers and mineralocorticoid receptor antagonists (P < 0.0001). Post‐discharge long‐term clinical outcomes after multivariate‐adjusted analysis revealed that women compared with men had lower all‐cause mortality [adjusted hazard ratio (aHR): 0.89, 95% confidence interval (CI): 0.84–0.93], lower cardiovascular mortality (aHR: 0.89, 95% CI: 0.80–0.99) and lower 1 year mortality (aHR: 0.91, 95% CI: 0.84–0.99) but similar HF rehospitalization rate (aHR: 1.02, 95% CI: 0.95–1.09) over 8 years of follow‐up. The superiority of women over men in all‐cause mortality was shown in HF with preserved EF (>50%) and HF with mildly reduced EF (40%–50%), but not in HF with reduced EF (<40%) category. Subgroup forest plot analysis showed body mass index, coexisting hypertension and chronic obstructive pulmonary disease as significant interacting factors.
Conclusions
With more coronary risk factors and medical comorbidities, less cardiac remodelling and better adherence to guideline‐directed HF therapy, women hospitalized for acute decompensated HF demonstrated superiority over men in long‐term post‐discharge clinical outcomes, including all‐cause mortality, cardiovascular mortality and 1 year mortality, and mainly in HF with preserved and mid‐range EF categories, in the Asian HF cohort.
Keywords: cohort study, heart failure, women
Introduction
Heart failure (HF) is the main cause of cardiovascular death and morbidity in the world. With the development of guideline‐directed medical therapy (GDMT) and global implementation, the mortality and quality of life in patients with HF have considerably improved in recent decades. The overall incidence of HF has been reported to be similar between women and men, with rates ranging from 20% to 33% before the age of 55 years. 1 , 2 However, a recent meta‐analysis study indicated that women had a 25% lower risk of HF and were older at the onset of HF than men. 3 Clinically, compared with male patients with HF, female patients with HF had more preserved left ventricular (LV) systolic function, had more medical comorbidities, were older in age and had a higher obesity prevalence. 4 Despite the similar risk of HF between women and men, previous clinical randomized trials and observational studies on HF treatment and outcomes have highly underrepresented the female population, particularly in clinical trials examining patients with HF with reduced ejection fraction (HFrEF). 5 , 6 Current international guidelines for HF 7 , 8 do not provide specific recommendations for different treatment strategies between women and men with HF or patients with different LV ejection fraction (LVEF) categories. Nevertheless, not only the targeted dosage of HF medications 9 but also the response after treatment could be different between women and men. 10 Further, the long‐term prognosis of HF may well vary between women and men in different populations. In the Global Research on Acute Conditions Team (GREAT) registry, 10 North Asian women were observed to have a better 1 year survival rate than men with HF. Two studies conducted in Japan have yet to demonstrate contradictory survival outcomes between women and men with HF. 11 , 12 However, no significant difference was observed in hospitalized HF outcomes between women and men in the European region. 13
To determine the significance of sex differences in Asians in the current era of GDMT implementation for HF, the present study aimed to retrospectively investigate the demographic characteristics, medical comorbidities, echocardiographic cardiac remodelling indices and GDMT adherence in association with subsequent long‐term clinical outcomes including all‐cause mortality, cardiovascular mortality and HF rehospitalization rate in a long‐term HF cohort in Taiwan.
Methods
The study protocol was approved by the Joint Institutional Review Board of Taipei Medical University (approval number: TMU‐JIRB No. N202109045) in Taipei, Taiwan.
This study retrospectively collected electronic medical records from Taipei Heart Institute (THI) and Taipei Medical University Clinical Research Database, which contains clinical information from three medical centres (Taipei Medical University Hospital, Wan Fang Hospital and Shuang Ho Hospital) affiliated with Taipei Medical University in northern Taiwan. Patients were not involved in the design, conduct, reporting or dissemination of the plans for this research. The diagnoses of HF and other comorbidities were established in accordance with the International Classification of Diseases, Ninth Revision, Clinical Modification and International Classification of Diseases, Tenth Revision, Clinical Modification codes. We excluded patients who were aged <20 years, had a previous HF diagnosis before the date of inclusion in the study, received HF treatment at the outpatient clinic and had a follow‐up period of <1 year. In total, 12 428 patients (6518 men and 5910 women) who were admitted to THI between 1 January 2011 and 31 November 2020 were enrolled. Medical comorbidities included in this study were hypertension, ischaemic heart disease, diabetes, hyperlipidaemia, atrial fibrillation (AF), chronic obstructive pulmonary disease (COPD), thyroid disease, chronic kidney disease (CKD) and valvular heart diseases. The GDMT for HF in the cohort followed the updated American College of Cardiology/American Heart Association, European Society of Cardiology and Taiwan Society of Cardiology HF guidelines including angiotensin‐converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta‐blockers, mineralocorticoid receptor antagonists (MRAs), angiotensin receptor–neprilysin inhibitors (ARNIs), sodium–glucose cotransporter‐2 inhibitors (SGLT2is), ivabradine, hydralazine, diuretic agents and nitrates.
Echocardiography assessment
According to the international consensus in HF classification, 7 , 8 HF with preserved ejection fraction (HFpEF) is defined as LVEF ≥ 50% on standard echocardiography, HF with mid‐range ejection fraction (HFmrEF) as LVEF 40%–49% and HFrEF as LVEF < 40%. The following echocardiographic parameters of cardiac remodelling were examined in each patient: LV end‐diastolic diameter (LVEDD), LV end‐systolic diameter (LVESD), interventricular septal diameter (IVSD), LV posterior wall (LVPW) thickness at the diastolic phase, maximal left atrial (LA) diameter, LV mass and LV mass index.
Definition of clinical outcomes
The long‐term clinical outcomes in the cohort included an incidence of cardiovascular mortality, all‐cause mortality and HF rehospitalization from 1 January 2011 to the end of the study period, that is, 31 November 2021.
Statistical analysis
All continuous data were expressed as the mean ± standard deviation. Categorical variables were presented as frequency and percentage. ANOVA was performed for intergroup comparisons. The χ 2 test was performed to compare categorical variables. Linear Cox regression and Kaplan–Meier analysis were performed to calculate hazard ratios (HRs) for long‐term clinical outcomes. Adjusted HRs (aHRs) were calculated after adjustment for potential confounding factors, namely, age, body mass index (BMI), LVEF, coexisting hypertension, ischaemic heart disease, diabetes mellitus, hyperlipidaemia, cerebrovascular disease, AF, COPD, CKD, mitral valve disease, and use of aspirin, statins, ACEIs, ARBs, MRAs, beta‐blockers, SGLT2is, ARNIs, ivabradine, hydralazine and diuretics. The 95% confidence intervals (CIs) of each HR and aHR were calculated. A P value of <0.05 was considered statistically significant in all analyses. Subgroup forest plot analysis in the whole HF cohort and in the HFrEF, HFmrEF and HFpEF categories was subsequently conducted to analyse the interaction of multiple medical comorbidities, including age, BMI, presence of ischaemic heart disease, hypertension, diabetes mellitus, hyperlipidaemia, cerebrovascular disease, AF, COPD and CKD stages, in relation with sex differences of long‐term clinical outcomes following hospitalized for acute decompensated HF.
Results
Baseline characteristics
In our cohort, female patients were significantly older than male patients (76.04 ± 13.43 vs. 71.12 ± 15.67 years, P < 0.0001). Women had a lower BMI than men (24.61 ± 5.04 vs. 24.90 ± 4.94 kg/m2, P = 0.0028). Moreover, a higher proportion of men were obese, with a BMI of >24 kg/m2 (P < 0.0001; Table 1).
Table 1.
Baseline demographic characteristics and medical comorbidities.
| All patients | Men | Women | P value* | ||||
|---|---|---|---|---|---|---|---|
| (n = 12 428) | (n = 6518) | (n = 5910) | |||||
| Age | 73.50 | 14.85 | 71.20 | 15.67 | 76.04 | 13.43 | <0.0001 |
| Age group | <0.0001 | ||||||
| 20–40 | 339 | 2.73% | 248 | 3.80% | 91 | 1.54% | |
| 40–60 | 2022 | 16.27% | 1347 | 20.67% | 675 | 11.42% | |
| 60–80 | 4973 | 40.01% | 2552 | 39.15% | 2421 | 40.96% | |
| 80–100 | 5056 | 40.68% | 2357 | 36.16% | 2699 | 45.67% | |
| 100+ | 38 | 0.31% | 14 | 0.21% | 24 | 0.41% | |
| Body weight (kg) | 63.11 | 15.02 | 68.23 | 15.21 | 57.46 | 12.60 | <0.0001 |
| Body height (cm) | 159.13 | 9.37 | 165.11 | 7.48 | 152.54 | 6.34 | <0.0001 |
| BMI | 24.76 | 4.99 | 24.90 | 4.94 | 24.61 | 5.04 | 0.0028 |
| <18 | 606 | 4.88% | 284 | 4.36% | 322 | 5.45% | <0.0001 |
| 18–24 | 4446 | 35.77% | 2261 | 34.69% | 2185 | 36.97% | |
| >24 | 5560 | 44.74% | 3018 | 46.30% | 2542 | 43.01% | |
| Comorbidities | |||||||
| Hypertension | 8419 | 67.74% | 4238 | 65.02% | 4181 | 70.74% | <0.0001 |
| Ischaemic heart disease | 1831 | 14.73% | 1094 | 16.78% | 737 | 12.47% | <0.0001 |
| Diabetes | 5046 | 40.60% | 2513 | 38.55% | 2533 | 42.86% | <0.0001 |
| Hyperlipidaemia | 3753 | 30.20% | 1892 | 29.03% | 1861 | 31.49% | 0.0028 |
| Cerebrovascular disease | 642 | 5.17% | 411 | 6.31% | 231 | 3.91% | <0.0001 |
| Atrial fibrillation | 2548 | 20.50% | 1288 | 19.76% | 1260 | 21.32% | 0.8184 |
| COPD | 1960 | 15.77% | 1322 | 20.28% | 638 | 10.80% | <0.0001 |
| Mitral valve disease | 1474 | 11.86% | 699 | 10.72% | 775 | 13.11% | <0.0001 |
| Aortic valve disease | 214 | 1.72% | 101 | 1.55% | 113 | 1.91% | 0.1208 |
| Tricuspid valve disease | 252 | 2.03% | 118 | 1.81% | 134 | 2.27% | 0.0711 |
| Pulmonary valve disease | 20 | 0.16% | 11 | 0.17% | 9 | 0.15% | 0.819 |
| Thyroid disease | 922 | 7.42% | 342 | 5.25% | 580 | 9.81% | <0.0001 |
| Chronic kidney disease | <0.0001 | ||||||
| Unknown | 811 | 6.53% | 466 | 7.15% | 345 | 5.84% | |
| Stage 1 | 753 | 6.06% | 453 | 6.95% | 300 | 5.08% | |
| Stage 2 | 3868 | 31.12% | 2391 | 36.68% | 1477 | 24.99% | |
| Stage 3 | 4620 | 37.17% | 2071 | 31.77% | 2549 | 43.13% | |
| Stage 4 | 1007 | 8.10% | 453 | 6.95% | 554 | 9.37% | |
| Stage 5 | 1369 | 11.02% | 684 | 10.49% | 685 | 11.59% | |
Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease.
Men versus women.
Medical comorbidities and relevant medications
Compared with men, women had higher rates of hypertension (70.74% vs. 65%, P < 0.0001), diabetes (42.86% vs. 38.55%, P < 0.0001), hyperlipidaemia (31.49% vs. 29.03%, P = 0.0028), mitral valve disease (13.11% vs. 10.72%, P < 0.0001) and thyroid disease (9.81% vs. 5.25%, P < 0.0001), but lower rates of ischaemic heart disease (12.47% vs. 16.78%, P < 0.0001), cerebrovascular disease (3.91% vs. 6.31%, P < 0.0001) and COPD (10.80% vs. 20.28%, P < 0.0001). Also, a higher proportion of women than that of men had moderate or advanced CKD. The prevalence of CKD stages 1–5 was 5.08%, 24.99%, 43.13%, 9.37% and 11.59% in women and 6.95%, 36.68%, 31.77%, 6.95% and 10.49% in men, respectively (P < 0.0001; Table 1). Regarding the adherence of HF GDMT, compared with men, women had significantly more prescriptions of all GDMT regimens including ACEIs, ARBs, MRAs, SGLT2is, ARNIs, ivabradine, diuretics and nitrates during hospitalization for acute decompensated HF (Table 2).
Table 2.
Heart failure medications in hospitalization.
| Medications | All patients | Men | Women | P value* | |||
|---|---|---|---|---|---|---|---|
| (n = 12 428) | (n = 6518) | (n = 5910) | |||||
| Aspirin | 9102 | 73.24% | 4130 | 63.36% | 4972 | 84.13% | <0.0001 |
| Statin | 6599 | 53.10% | 3145 | 48.25% | 3454 | 58.44% | 0.8034 |
| ACEI | 4732 | 38.08% | 2361 | 36.22% | 2371 | 40.12% | <0.0001 |
| ARB | 8999 | 72.41% | 4340 | 66.58% | 4659 | 78.83% | 0.0148 |
| Beta‐blockers | 9017 | 72.55% | 4308 | 66.09% | 4709 | 79.68% | 0.4193 |
| MRA | 6231 | 50.14% | 2978 | 45.69% | 3253 | 55.04% | 0.5921 |
| SGLT2i | 407 | 10.39% | 158 | 7.45% | 249 | 13.87% | <0.0001 |
| ARNI | 813 | 27.54% | 275 | 17.52% | 538 | 38.93% | <0.0001 |
| Ivabradine | 516 | 6.96% | 171 | 4.31% | 345 | 10.00% | <0.0001 |
| Hydralazine | 2320 | 18.67% | 1218 | 18.69% | 1102 | 18.65% | <0.0001 |
| Diuretics | 11 034 | 88.78% | 5330 | 81.77% | 5704 | 96.51% | <0.0001 |
| Nitrates | 8762 | 70.50% | 4103 | 62.95% | 4659 | 78.83% | 0.0121 |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium–glucose cotransporter‐2 inhibitor.
Men versus women.
Echocardiography findings
Compared with men, women had a higher LVEF (61.07% vs. 55.78%, P < 0.0001) during initial HF hospitalization. In terms of HF categories, women had a higher proportion of HFpEF (LVEF > 50%) and a lower proportion with HFmrEF (LVEF 40%–50%) and HFrEF (LVEF < 40%) compared with men (women vs. men: 8.19% vs. 15.23%, 8.58% vs. 12.55% and 63.84% vs. 51.60% in HFrEF, HFmrEF and HFpEF, respectively, P < 0.0001). Echocardiography for cardiac remodelling revealed a smaller LV chamber size and less LV wall thickness for women than men (46.47 ± 7.77 vs. 50.70 ± 8.57 mm for LVEDD, P < 0.0001; 31.08 ± 8.41 vs. 35.67 ± 9.93 mm for LVESD, P < 0.0001; 12.03 ± 2.47 vs. 12.44 ± 2.51 mm for IVSD, P < 0.0001; and 11.78 ± 2.33 vs. 12.27 ± 2.37 mm for LVPW thickness, P < 0.0001, respectively). Also, women had a smaller LA chamber diameter (41.39 ± 8.00 vs. 42.34 ± 7.99 mm, P < 0.0001). Although having lower LV mass, women had significantly larger LV mass index than men (women vs. men: 213.26 ± 77.69 vs. 257.24 ± 93.24 g, for LV mass, P < 0.0001, and 90.38 ± 35.03 vs. 84.67 ± 31.73 g/m2, for LV mass index, P < 0.0001, respectively; Table 3).
Table 3.
Echocardiographic indices in hospitalization for acute decompensated heart failure.
| All patients | Men | Women | P value* | ||||
|---|---|---|---|---|---|---|---|
| (n = 12 428) | (n = 6518) | (n = 5910) | |||||
| LVEF | 58.32 | 15.28 | 55.78 | 15.86 | 61.07 | 14.12 | <0.0001 |
| LVEF | <0.0001 | ||||||
| Unknown | 2490 | 20.04% | 1344 | 20.62% | 1146 | 19.39% | |
| <40% | 1477 | 11.88% | 993 | 15.23% | 484 | 8.19% | |
| 40%–50% | 1325 | 10.66% | 818 | 12.55% | 507 | 8.58% | |
| >50% | 7136 | 57.42% | 3363 | 51.60% | 3773 | 63.84% | |
| Echocardiography parameters | |||||||
| LVEDD (mm) | 48.66 | 8.46 | 50.70 | 8.57 | 46.47 | 7.77 | <0.0001 |
| LVESD (mm) | 33.47 | 9.51 | 35.67 | 9.93 | 31.08 | 8.41 | <0.0001 |
| IVSD (mm) | 12.24 | 2.50 | 12.44 | 2.51 | 12.03 | 2.47 | <0.0001 |
| LVPW thickness (mm) | 12.04 | 2.37 | 12.27 | 2.39 | 11.78 | 2.33 | <0.0001 |
| LA diameter (mm) | 41.88 | 8.01 | 42.34 | 7.99 | 41.39 | 8.00 | <0.0001 |
| LV mass (g) | 236.10 | 88.87 | 257.24 | 93.24 | 213.26 | 77.69 | <0.0001 |
| LV mass index (g/m2) | 87.42 | 33.48 | 84.67 | 31.73 | 90.38 | 35.03 | <0.0001 |
Abbreviations: IVSD, interventricular septal diameter; LA, left atrial; LV, left ventricular; LVEDD, left ventricular end‐diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end‐systolic diameter; LVPW, left ventricular posterior wall.
Men versus women.
Long‐term outcomes after index HF hospitalization
The mean follow‐up durations of the women and men were 3.22 ± 2.77 and 3.18 ± 2.74 years, respectively. Univariate analysis revealed that age, BMI, hypertension, diabetes, hyperlipidaemia, COPD, mitral valve disease, thyroid disease, CKD, and use of aspirin, statin, ACEI, ARB, beta‐blocker, SGLT2i, ARNI and diuretics were predictive of all‐cause mortality during the follow‐up period. Multivariate aHR analysis of long‐term outcomes revealed that women overall had significantly lower risks of all‐cause mortality (aHR: 0.89, 95% CI: 0.84–0.93, P < 0.001), cardiovascular mortality (aHR: 0.89, 95% CI: 0.80–0.99, P = 0.028) and 1 year mortality (aHR: 0.91, 95% CI: 0.84–0.99, P = 0.022; Table 4 and Figure 1A–C) compared with men in acute decompensated HF patients needing hospitalization in the cohort. However, there was no difference in mortality during HF hospitalization nor in HF rehospitalization rate between women and men (aHR: 0.91, 95% CI: 0.78–1.05, P = 0.186, and aHR: 1.02, 95% CI: 0.95–1.09, P = 0.641, respectively; Table 4 and Figure 1D,E) in the cohort.
Table 4.
Unadjusted and adjusted hazard ratios of long‐term clinical outcomes between women and men hospitalized for acute decompensated heart failure.
| Outcome | Crude HR (95% CI) | P value | Adjusted a HR (95% CI) | P value |
|---|---|---|---|---|
| All‐cause mortality | 1.04 (0.99–1.09) | 0.1021 | 0.89 (0.84–0.93) | <0.0001 |
| Cardiovascular mortality | 0.95 (0.87–1.04) | 0.2421 | 0.89 (0.80–0.99) | 0.0289 |
| Mortality during admission | 0.95 (0.85–1.06) | 0.3581 | 0.91 (0.78–1.05) | 0.1869 |
| Mortality in the first year | 0.99 (0.93–1.06) | 0.7916 | 0.91 (0.84–0.99) | 0.0223 |
| Rehospitalization | 1.03 (0.97–1.10) | 0.2863 | 1.02 (0.95–1.09) | 0.6415 |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium–glucose cotransporter‐2 inhibitor.
This analysis was adjusted for age, BMI, hypertension, ischaemic heart disease, diabetes, hyperlipidaemia, cerebrovascular disease, atrial fibrillation, COPD, mitral valve disease, aspirin, statin, ACEI, ARB, beta‐blocker, MRA, SGLT2i, ARNI, ivabradine, hydralazine, diuretics and CKD stage.
Figure 1.
Linear Cox regression and Kaplan–Meier curves compared between women and men hospitalized for heart failure (HF) in (A) all‐cause mortality, (B) 1 year mortality, (C) cardiovascular mortality, (D) freedom from HF rehospitalization and (E) mortality during hospitalization for acute decompensated HF.
Long‐term outcomes after index HF hospitalization also differed between women and men in different HF categories. Among patients with HFpEF (LVEF > 50%), women exhibited significantly lower long‐term all‐cause mortality and mortality during index hospitalization (aHR: 0.90, 95% CI: 0.84–0.97, P = 0.003, and aHR: 0.80, 95% CI: 0.65–1.00, P = 0.044, Table 5), but not in long‐term cardiovascular mortality and HF rehospitalization rate. In patients with HFmrEF (LVEF 40%–50%), women also had significantly lower long‐term all‐cause mortality and 1 year mortality than men (aHR: 0.84, 95% CI: 0.72–0.97, P = 0.017, and aHR: 0.78, 95% CI: 0.63–0.98, P = 0.036, Table 5). In contrast, no difference in long‐term all‐cause mortality, cardiovascular mortality, 1 year mortality, mortality during the index hospitalization and long‐term HF rehospitalization rate was noted between women and men in the HFrEF category (Table 5).
Table 5.
Unadjusted and adjusted hazard ratios of long‐term clinical outcomes between women and men hospitalized for heart failure with reduced, mid‐range and preserved ejection fraction.
| LVEF < 40% (n = 1477) | LVEF 40%–50% (n = 1325) | LVEF > 50% (n = 7136) | ||||
|---|---|---|---|---|---|---|
| Outcomes | Adjusted a HR (95% CI) | P value | Adjusted a HR (95% CI) | P value | Adjusted a HR (95% CI) | P value |
| All‐cause mortality | 0.78 (1.05–0.19) | 0.1861 | 0.72 (0.97–0.02) | 0.0174 | 0.84 (0.97–0.00) | 0.0032 |
| Cardiovascular mortality | 0.63 (1.02–0.07) | 0.0669 | 0.58 (1.01–0.06) | 0.0593 | 0.82 (1.11–0.55) | 0.5535 |
| Mortality during admission | 0.78 (1.99–0.36) | 0.3649 | 0.55 (1.42–0.60) | 0.5982 | 0.65 (1.00–0.04) | 0.0446 |
| Mortality in the first year | 0.75 (1.17–0.57) | 0.5704 | 0.63 (0.98–0.04) | 0.036 | 0.83 (1.03–0.15) | 0.1507 |
| Rehospitalization | 0.72 (1.03–0.09) | 0.0915 | 0.85 (1.22–0.87) | 0.8704 | 0.98 (1.16–0.16) | 0.1562 |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium–glucose cotransporter‐2 inhibitor.
This analysis was adjusted for age, BMI, hypertension, ischaemic heart disease, diabetes, hyperlipidaemia, cerebrovascular disease, atrial fibrillation, COPD, mitral valve disease, aspirin, statin, ACEI, ARB, beta‐blocker, MRA, SGLT2i, ARNI, ivabradine, hydralazine, diuretics and CKD stage.
In forest plot subgroup analysis, long‐term all‐cause mortality between men and women in the cohort was significantly interacted by BMI, coexisting hypertension and COPD, but not by age, presence of ischaemic heart disease, diabetes, cerebrovascular disease, AF or CKD stages (Figure 2A). BMI < 18 kg/m2 significantly favoured women's survival (P = 0.067) in the HFrEF category, whereas BMI > 24 kg/m2 borderline favoured men's survival (P = 0.055) only in the HFpEF category. The presence of hypertension disfavoured women's survival (P = 0.0358) only in the HFpEF category. The presence of COPD disfavoured men's survival (P = 0.0072) in both the HFmrEF and HFpEF categories. In regard to 1 year mortality, BMI > 24 kg/m2 significantly favoured men's survival over women in the HFpEF category, whereas the presence of moderate CKD (stages 2 and 4) favoured women's survival in the HFpEF category (Figure 2B). In cardiovascular mortality, only the presence of AF favoured men's survival in the whole cohort but not in the individual HF category (Figure 2C). As to HF rehospitalization, the presence of COPD significantly favoured men free from rehospitalization, but only in the HFpEF category (Figure 2D). For in‐hospital mortality, there was no significant interacting factor in any HF category (Figure 2E).
Figure 2.
Subgroup forest plot analysis of (A) all‐cause mortality, (B) cardiovascular mortality, (C) mortality during hospitalization for acute decompensated heart failure (HF), (D) 1 year mortality and (E) HF rehospitalization rate compared between female and male hospitalized HF patients in total HF population and among HF with reduced ejection fraction (EF) [left ventricular ejection fraction (LVEF) <40%], mid‐range EF (LVEF 40%–50%) and preserved EF (LVEF > 50%) categories. BMI, body mass index; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease.
Discussion
Main findings
The main findings of this study were as follows: First, in the present cohort of hospitalized acute decompensated HF patients, women compared with men belonged more to the HFpEF (LVEF > 50%) category and less to the HFmrEF (LVEF 40%–50%) or HFrEF (LVEF < 40%) category. Second, in long‐term outcomes after the index HF hospitalization, women compared with men demonstrated significantly lower long‐term all‐cause mortality, 1 year mortality and cardiovascular mortality, but not in‐hospital mortality during index HF hospitalization or HF rehospitalization rate. Third, women had significantly higher adherence to GDMT for HF in all ejection fraction (EF) spectrum HF, including ACEIs, ARBs, ARNIs, beta‐blockers, MRAs, SGLT2is and ivabradine compared with men during acute HF hospitalization in the cohort. Fourth, women demonstrated better long‐term outcomes than men mainly in the HFpEF and HFmrEF categories, but not in the HFrEF category. Fifth, in subgroup forest plot analysis, long‐term all‐cause mortality in the cohort was significantly interacted by BMI, coexisting hypertension and COPD, but not by age, presence of ischaemic heart disease, cerebrovascular disease, diabetes mellitus, CKD stages or AF. Lower BMI below 18 kg/m2 favoured women's survival in the HFrEF and HFmrEF categories. The presence of hypertension favoured men's survival in the HFpEF category, while coexisting COPD did not favour men's survival in the HFpEF and HFmrEF categories.
Differences in clinical characteristics and comorbidities between women and men hospitalized for acute decompensated HF
Women with HF have been reported to have more medical comorbidities and were older in age at the time of HF diagnosis. 4 A nationwide retrospective study in the Netherlands 14 reported that the prevalence of ischaemic heart disease was significantly higher in female patients. Similar findings have been reported for patients with HF from Japan. 11 , 12 However, the most recent global REPORT‐HF (Registry to Assess Medical Practice with Longitudinal Observation for the Treatment of Heart Failure) study 15 reported that women hospitalized for HF had more coexisting hypertension, diabetes, valvular heart disease and AF/atrial flutter but less coronary artery disease and CKD than men. In the present mainly Asian cohort of hospitalized HF patients, we demonstrated a higher prevalence of hypertension, diabetes, hyperlipidaemia, thyroid disease and moderate to severe CKD stages in women, contrasting with the higher prevalence of ischaemic heart disease, cerebrovascular disease and COPD in men. The difference in underlying comorbidities might well be attributed to different mechanisms and manifestations of HF between men and women. The risk of coronary microvascular disease or reduced coronary microvascular reserve had been demonstrated to be higher in women than in men and proportional to the burden of cardiovascular risk factors. 16 Coronary microvascular reserve has been reported to be strongly associated with the incidence of HF, especially in patients with HFpEF. 17 , 18 On the other hand, we observed no evidence of obesity paradox or bonus in HFrEF or any EF category in the present Asian cohort, in contrast to that of the Western population. 19 , 20 , 21 In subgroup forest plot analysis, despite a significantly higher proportion of men than women being overweight (BMI > 24 kg/m2), there was no difference in long‐term outcomes noted between women and men in the range of BMI between 18 and 24 kg/m2 and >24 kg/m2. Instead, compared with men, lower all‐cause mortality was noted in women with a BMI of <18 kg/m2 in the HFrEF category but not in the higher BMI range. The issue of the obesity paradox among different genders might need further verification.
Sex differences in GDMT adherence and long‐term outcomes after index HF hospitalization
Previous long‐term observational studies regarding sex differences in clinical outcomes after HF hospitalization have been inconsistent. Blumer et al. 22 noted no difference in the mortality rate 30 and 180 days after symptomatic HF hospitalization between women and men. Stolfo et al. 23 reported that women had a significantly lower risk of all‐cause mortality in the HFrEF, HFmrEF and HFpEF categories. Wideqvist et al. 24 analysed a total of 62 228 Swedish people with HF, and the results revealed that women had a lower 1 year mortality risk compared with men after adjusting age. Sotomi et al. 11 reported that women with HFpEF had higher risks of all‐cause death and HF readmission than did men in Japan. Dewan et al. 25 reported no difference in long‐term outcomes between women and men in Korea, irrespective of their LVEF status. 22 The global REPORT‐HF study 15 showed no difference in 1 year all‐cause mortality between men and women hospitalized for acute HF in countries of middle and highest income tertiles, but better outcome for women in countries with the lowest income tertile. On the other hand, women had been repeatedly reported with less adherence to GDMT for HF than men in several clinical trials 13 , 22 and registry observations including the REPORT‐HF study. 15 , 26 , 27 A meta‐analysis involving 25 randomized controlled trials and over 100 000 patients found no significant differences in treatment outcomes between men and women with HF for GDMT medications, in terms of all‐cause mortality and HF hospitalization. 28 These studies highlight the consistent efficacy of these therapies between sexes and underscore the need for balanced sex representation in clinical trials to better understand the full impact of HF treatments across the population. In the present mainly Asian cohort, we demonstrated that women hospitalized for acute decompensated HF had a significantly lower risk of all‐cause death, cardiovascular mortality and 1 year mortality, but not a long‐term HF rehospitalization rate or mortality during index HF hospitalization. Further LVEF stratification disclosed that women were shown to have significantly better long‐term outcomes in all‐cause death and cardiovascular death in the HFpEF and HFmrEF categories but not in the HFrEF category. The difference as compared with previous studies might well be attributed to significantly better adoption and adherence of GDMT medications in female than male patients hospitalized for HF in the cohort, which included ACEIs, ARBs, ARNIs, beta‐blockers, MRAs, SGLT2is and ivabradine in addition to aspirin and statins for underlying atherosclerotic heart diseases.
Sex differences in cardiac remodelling patterns in decompensated HF needing hospitalization
In this study, compared with men, women were more likely to have concentric LV hypertrophy, smaller chamber sizes and preserved LVEF consistent with recent observational studies in the Asian population. 11 , 22 Several mechanisms may underlie the differences in cardiac remodelling patterns between women and men with HF. First, oestrogen prevents hypertrophic changes in the heart, 29 whereas the reduction of oestrogen protection after menopause might contribute to changes in LV structure, leading to substantial diastolic dysfunction in the heart. 30 From animal studies and limited human data, oestrogen may have potential protective cardiac effects, while testosterone could potentially exacerbate cardiac issues. However, despite plausible biological mechanisms and animal data supporting these effects, human studies provide mixed results and lack comprehensive prospective trials. 31 Second, the pattern of cardiac fibrotic changes in advanced age differs between men and women. Eccentric LV hypertrophy, collagen I predominance and increased platelet‐derived growth factor receptor alpha expression were observed in the hearts of older male mice in experiments. 30 In vivo, men also had higher circulating cardiovascular proteins associated with adverse cardiac remodelling (e.g., matrix metalloproteinase‐3 and suppression of tumourigenesis‐2) compared with women. 32 Clinically, women with isolated systolic hypertension had increased LV wall thickness and LV mass but a normal chamber size, whereas men with isolated systolic hypertension had increased LV mass accompanied with chamber dilatation. 33 Moreover, among patients with increased arterial stiffness, a significant risk of abnormal LV global longitudinal strain was observed in female patients. 34 In the present cohort, we observed higher prevalence of cardiovascular risk factors or comorbidities in hospitalized HF women than in men, including hypertension, diabetes, hyperlipidaemia and moderate to severe CKD, which could cause higher risk of increased arterial stiffness in women. The resultant difference in cardiac remodelling patterns between women and men might as well contribute significantly to more clinical HFpEF manifestation but less HFrEF in hospitalized HF patients and better long‐term outcomes in the present cohort observation.
Limitations
This study had inevitable limitations such as those of a retrospective observational cohort. First, we included only patients who were hospitalized because of acute decompensated HF. The characteristics of the enrolled patients in the study might differ from those of stable HF properly managed in outpatient clinics. Second, long‐term adherence and titration of GDMT medications during outpatient clinic follow‐up or repeated HF hospitalization were not tracked and analysed. Variations in HF medications might affect long‐term therapeutic outcomes after discharge from acute HF hospitalization. Third, because of the limitations of the database, information on nonpharmacological HF management, including cardiac resynchronization therapy, LV assist device use and cardiac rehabilitation, was not included. Fourth, the present cohort enrolled a mainly Asian population with decompensated HF needing hospitalization. Differences with other racial populations warrant further comparative studies in the future.
Conclusions
With older age, higher rates of coexisting hypertension, diabetes, hyperlipidaemia and moderate to severe CKD, but better adherence to guideline‐directed HF medications, minor cardiac remodelling and better LVEF, women demonstrated better long‐term outcomes including all‐cause mortality, cardiovascular mortality and 1 year mortality except HF rehospitalization rate over 8 years of follow‐up in the present Asian HF cohort. The superiority of women over men in long‐term survival after discharge for acute decompensated HF resided mainly in HF with preserved and mildly reduced EF categories although similar in HF with reduced EF category. Body weight index, coexisting hypertension and COPD were significant interacting factors.
Chen, C.‐C. , Chiu, C.‐C. , Hao, W.‐R. , Hsu, M.‐H. , Liu, J.‐C. , and Lin, J.‐L. (2024) Sex differences in clinical characteristics and long‐term clinical outcomes in Asian hospitalized heart failure patients. ESC Heart Failure, 11: 3095–3104. 10.1002/ehf2.14888.
References
- 1. Lloyd‐Jones DM, Larson MG, Leip EP, Beiser A, D'Agostino RB, Kannel WB, et al. Lifetime risk for developing congestive heart failure: The Framingham Heart Study. Circulation 2002;106:3068‐3072. doi: 10.1161/01.CIR.0000039105.49749.6F [DOI] [PubMed] [Google Scholar]
- 2. Bleumink GS, Knetsch AM, Sturkenboom MC, Straus SM, Hofman A, Deckers JW, et al. Quantifying the heart failure epidemic: Prevalence, incidence rate, lifetime risk and prognosis of heart failure: The Rotterdam Study. Eur Heart J 2004;25:1614‐1619. doi: 10.1016/j.ehj.2004.06.038 [DOI] [PubMed] [Google Scholar]
- 3. Suthahar N, Lau ES, Blaha MJ, Paniagua SM, Larson MG, Psaty BM, et al. Sex‐specific associations of cardiovascular risk factors and biomarkers with incident heart failure. J Am Coll Cardiol 2020;76:1455‐1465. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Lam CSP, Arnott C, Beale AL, Chandramouli C, Hilfiker‐Kleiner D, Kaye DM, et al. Sex differences in heart failure. Eur Heart J 2019;40:3859‐3868c. doi: 10.1093/eurheartj/ehz835 [DOI] [PubMed] [Google Scholar]
- 5. Tahhan AS, Vaduganathan M, Greene SJ, Fonarow GC, Fiuzat M, Jessup M, et al. Enrollment of older patients, women, and racial and ethnic minorities in contemporary heart failure clinical trials: A systematic review. JAMA Cardiol 2018;3:1011‐1019. doi: 10.1001/jamacardio.2018.2559 [DOI] [PubMed] [Google Scholar]
- 6. Aimo A, Vergaro G, Barison A, Maffei S, Borrelli C, Morrone D, et al. Sex‐related differences in chronic heart failure. Int J Cardiol 2018;255:145‐151. doi: 10.1016/j.ijcard.2017.10.068 [DOI] [PubMed] [Google Scholar]
- 7. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022;145:e895‐e1032. doi: 10.1161/CIR.0000000000001063 [DOI] [PubMed] [Google Scholar]
- 8. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2021;42:3599‐3726. doi: 10.1093/eurheartj/ehab368 [DOI] [PubMed] [Google Scholar]
- 9. Santema BT, Ouwerkerk W, Tromp J, Sama IE, Ravera A, Regitz‐Zagrosek V, et al. Identifying optimal doses of heart failure medications in men compared with women: A prospective, observational, cohort study. Lancet 2019;394:1254‐1263. doi: 10.1016/S0140-6736(19)31792-1 [DOI] [PubMed] [Google Scholar]
- 10. Teixeira A, Parenica J, Park JJ, Ishihara S, AlHabib KF, Laribi S, et al. Clinical presentation and outcome by age categories in acute heart failure: Results from an international observational cohort. Eur J Heart Fail 2015;17:1114‐1123. doi: 10.1002/ejhf.330 [DOI] [PubMed] [Google Scholar]
- 11. Sotomi Y, Hikoso S, Nakatani D, Mizuno H, Okada K, Dohi T, et al. Sex differences in heart failure with preserved ejection fraction. J Am Heart Assoc 2021;10:e018574. doi: 10.1161/JAHA.120.018574 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Yamamoto E, Kato T, Yaku H, Morimoto T, Inuzuka Y, Tamaki Y, et al. Sex differences in patients with acute decompensated heart failure in Japan: Observation from the KCHF registry. ESC Heart Fail 2020;7:2485‐2493. doi: 10.1002/ehf2.12815 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Motiejūnaitė J, Akiyama E, Cohen‐Solal A, Maggioni AP, Mueller C, Choi DJ, et al. The association of long‐term outcome and biological sex in patients with acute heart failure from different geographic regions. Eur Heart J 2020;41:1357‐1364. doi: 10.1093/eurheartj/ehaa071 [DOI] [PubMed] [Google Scholar]
- 14. Gürgöze MT, van der Galiën OP, Limpens MAM, Roest S, Hoekstra RC, IJpma AS, et al. Impact of sex differences in co‐morbidities and medication adherence on outcome in 25 776 heart failure patients. ESC Heart Fail 2021;8:63‐73. doi: 10.1002/ehf2.13113 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Tromp J, Ezekowitz JA, Ouwerkerk W, Chandramouli C, Yiu KH, Angermann CE, et al. Global variations according to sex in patients hospitalized for heart failure in the REPORT‐HF registry. J Am Coll Cardiol HF 2023;11:1262‐1271. [DOI] [PubMed] [Google Scholar]
- 16. Taqueti VR, Di Carli MF. Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state‐of‐the‐art review. J Am Coll Cardiol 2018;72:2625‐2641. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Kaze AD, Santhanam P, Erqou S, Ahima RS, Bertoni A, Echouffo‐Tcheugui JB. Microvascular disease and incident heart failure among individuals with type 2 diabetes mellitus. J Am Heart Assoc 2021;10:e018998. doi: 10.1161/JAHA.120.018998 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Rush CJ, Berry C, Oldroyd KG, Rocchiccioli JP, Lindsay MM, Touyz RM, et al. Prevalence of coronary artery disease and coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction. JAMA Cardiol 2021;6:1130‐1143. doi: 10.1001/jamacardio.2021.1825 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Vest AR, Wu Y, Hachamovitch R, Young JB, Cho L. The heart failure overweight/obesity survival paradox: The missing sex link. JACC Heart Fail 2015;3:917‐926. doi: 10.1016/j.jchf.2015.06.009 [DOI] [PubMed] [Google Scholar]
- 20. Kenchaiah S, Pocock SJ, Wang D, Finn PV, Zornoff LAM, Skali H, et al. Body mass index and prognosis in patients with chronic heart failure: Insights from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation 2007;116:627‐636. doi: 10.1161/CIRCULATIONAHA.106.679779 [DOI] [PubMed] [Google Scholar]
- 21. Sharma A, Lavie CJ, Borer JS, Vallakati A, Goel S, Lopez‐Jimenez F, et al. Meta‐analysis of the relation of body mass index to all‐cause and cardiovascular mortality and hospitalization in patients with chronic heart failure. Am J Cardiol 2015;115:1428‐1434. doi: 10.1016/j.amjcard.2015.02.024 [DOI] [PubMed] [Google Scholar]
- 22. Blumer V, Greene SJ, Wu A, Butler J, Ezekowitz JA, Lindenfeld JA, et al. Sex differences in clinical course and patient‐reported outcomes among patients hospitalized for heart failure. JACC Heart Fail 2021;9:336‐345. doi: 10.1016/j.jchf.2020.12.011 [DOI] [PubMed] [Google Scholar]
- 23. Stolfo D, Uijl A, Vedin O, Strömberg A, Faxén UL, Rosano GMC, et al. Sex‐based differences in heart failure across the ejection fraction spectrum: Phenotyping, and prognostic and therapeutic implications. JACC: Heart Failure 2019;7:505‐515. doi: 10.1016/j.jchf.2019.03.011 [DOI] [PubMed] [Google Scholar]
- 24. Wideqvist M, Rosengren A, Schaufelberger M, Pivodic A, Fu M. Ten year age‐ and sex‐specific temporal trends in incidence and prevalence of heart failure in Västra Götaland, Sweden. ESC Heart Fail 2022;9:3931‐3941. doi: 10.1002/ehf2.14103 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Dewan P, Rorth R, Jhund PS, Shen L, Raparelli V, Petrie MC, et al. Differential impact of heart failure with reduced ejection fraction on men and women. J Am Coll Cardiol 2019;73:29‐40. [DOI] [PubMed] [Google Scholar]
- 26. Lainscak M, Milinkovic I, Polovina M, et al. Sex‐ and age‐related differences in the management and outcomes of chronic heart failure: An analysis of patients from the ESC HFA EORP Heart Failure Long‐Term Registry. Eur J Heart Fail 2020;22:92‐102. doi: 10.1002/ejhf.1645 [DOI] [PubMed] [Google Scholar]
- 27. Donaldson C, Eder S, Baker C, Aronovitz MJ, Weiss AD, Hall‐Porter M, et al. Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor‐dependent pathway that increases calcineurin degradation. Circ Res 2009;104:265‐275. doi: 10.1161/CIRCRESAHA.108.190397 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Danielson C, Lileikyte G, Ouwerkerk W, et al. Sex differences in efficacy of pharmacological therapies in heart failure with reduced ejection fraction: A meta‐analysis. ESC Heart Fail 2022;9:2753‐2761. doi: 10.1002/ehf2.13974 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Maslov PZ, Kim JK, Argulian E, et al. Is cardiac diastolic dysfunction a part of post‐menopausal syndrome? JACC: Heart Failure 2019;7:192‐203. doi: 10.1016/j.jchf.2018.12.018 [DOI] [PubMed] [Google Scholar]
- 30. Achkar A, Saliba Y, Fares N. Differential gender‐dependent patterns of cardiac fibrosis and fibroblast phenotypes in aging mice. Oxid Med Cell Longev 2020;2020:8282157. doi: 10.1155/2020/8282157 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. De Smet MA, Lapauw B, De Backer T. Sex steroids in relation to cardiac structure and function in men. Andrologia 2017;49: doi: 10.1111/and.12610 [DOI] [PubMed] [Google Scholar]
- 32. de Bakker M, Loncq de Jong M, Petersen T, de Lange I, Akkerhuis KM, Umans VA, et al. Sex‐specific cardiovascular protein levels and their link with clinical outcome in heart failure. ESC Heart Failure 2024;11:594‐600. doi: 10.1002/ehf2.14578 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Krumholz HM, Larson M, Levy D. Sex differences in cardiac adaptation to isolated systolic hypertension. Am J Cardiol 1993;72:310‐313. doi: 10.1016/0002-9149(93)90678-6 [DOI] [PubMed] [Google Scholar]
- 34. Yoshida Y, Nakanishi K, Daimon M, Ishiwata J, Sawada N, Hirokawa M, et al. Sex‐specific difference in the association between arterial stiffness and subclinical left ventricular dysfunction. Eur Heart J Cardiovasc Imaging 2021;22:817‐823. doi: 10.1093/ehjci/jeaa156 [DOI] [PubMed] [Google Scholar]