Gender and Survival in Patients With Heart Failure
Gender and Survival in Patients With Heart Failure
Data were available from 31 studies involving a total of 54 416 patients. Of these, 1179 patients were excluded from the analysis due to irresolvable dates or having died during an index hospital admission, 2246 based on aetiology of HF (either valvular heart disease or hypertrophic cardiomyopathy), 9019 due to missing information on left ventricular EF, and 23 due to missing information on sex. Thus, the main analysis was based on 41 949 patients; 28 052 (67%) men and 13 897 (33%) women.
The baseline characteristics of the study population are shown in Table 1. When compared with men, women were older {70.5 [standard deviation (SD) 12.1] vs. 65.6 [SD 11.6] years}, more commonly had a history of hypertension (49.9% vs. 40.0%), and less commonly had a reduced EF (62.6% vs. 81.6%). Women had more severe functional limitation than men, with a greater proportion of women than men in New York Heart Association (NYHA) class III or IV. Mean heart rate was also higher in women. Overall, women were prescribed angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and beta-blockers less frequently than men. The under-use in women of these treatments was particularly evident in patients with reduced EF (ACE inhibitors or ARBs 79.0% vs. 84.6%; beta-blocker 36.2% vs. 39.7%).
During 3 years follow-up, 3521 (25.3%) women and 7232 (25.7%) men died. There were 137 [95% confidence interval (CI) 133–140] deaths per 1000 patient-years in men and 135 (95% CI 131–139) deaths per 1000 patient-years in women. On analysis only adjusted for age, men were at higher risk of death than women [hazard ratio (HR) 1.31, 95% CI 1.25–1.36] (Figure 1). As previously reported, on multivariable analysis, male sex showed an independent association with the risk of death at 3 years (HR 1.23, 95% CI 1.18–1.28). When the randomized controlled trials of pharmacotherapy (three trials, 20 878 patients) were excluded from the analysis, the risk of death remained higher among men (fully adjusted HR 1.27, 95% CI 1.19–1.36).
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Figure 1.
All-cause mortality for men and women adjusted for age (P < 0.001).
The excess mortality risk associated with male sex was of similar magnitude in patients with reduced or preserved EF (Figure 2). Neither age (P = 0.63) nor history of hypertension (P = 0.10) altered the differential relationship between sex and outcome. However, both diabetes (P < 0.001) and aetiology of HF (P = 0.03) did appear to modify this relationship.
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Figure 2.
All-cause mortality for men and women with heart failure and preserved ejection fraction (HF-PEF) or reduced ejection fraction (HF-REF) adjusted for age (EF group × gender interaction P = 0.72).
Diabetes was present more frequently in women (25.4%) than in men (22.8%, P < 0.001). In patients with reduced EF, diabetes was present among 26.6% of women and 23.1% of men (P < 0.001), and in patients with preserved EF, among 23.6% of women and 21.7% of men (P = 0.03). There were 2997 deaths among 9776 patients (30.7%) with, and 7366 deaths among 31 513 patients (23.4%) without, diabetes. After adjustment for covariates, diabetes retained an independent association with death from any cause (adjusted HR 1.41, 95% CI 1.35–1.47) and with cardiovascular death (HR 1.51, 95% CI 1.41–1.62).
Concomitant diabetes attenuated the lower risk of death associated with female sex (risk of death for men vs. women: diabetes HR 1.11, 95% CI 1.03–1.20; no diabetes 1.37, 95% CI 1.30–1.45, P-value for interaction <0.0001). Diabetes also appeared to modify the relationship between sex and mortality, irrespective of left ventricular EF. Among patients with diabetes, there was no statistically significant difference in the HR for death from any cause between men and women in either the preserved or reduced EF groups. However, for patients without diabetes, men had a higher risk of death from any cause compared with women, in both the preserved and reduced EF groups. The adjusted HR for different subgroups, with women with preserved EF and no diabetes as the comparator, is shown in Figure 3A. The three-way interaction for gender ×EF ×diabetes was not statistically significant (P = 0.208).
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Figure 3.
(A) Risk of death of heart failure (HF) patients by sex, diabetes mellitus (DM), and ejection fraction group (preserved HF-PEF or reduced HF-REF) adjusted for age and stratified by study (gender × EF group × diabetes interaction P = 0.208). (B) Risk of death of HF patients by sex, aetiology, and ejection fraction group (HF-PEF or HF-REF) adjusted for age and stratified by study (gender × EF group × ischaemic aetiology interaction P = 0.0008). CI, confidence interval.
Ischaemic aetiology was less frequent among women (46.3%) than men (58.7%, P < 0.001). Ischaemic aetiology was recorded in 61.4% of men and 50.9% of women (P < 0.001) with reduced EF, and in 46.9% of men and 38.6% of women (P < 0.001) with preserved EF. Ischaemic aetiology showed an independent association with death from any cause (adjusted HR 1.07, 95% CI 1.03–1.12), and cardiovascular death (HR 1.11, 95% CI 1.04–1.19).
The aetiology of HF appeared to modify the association between sex and outcome: risk of death for men vs. women with ischaemic HF, adjusted HR 1.17 (95% CI 1.10–1.24); non-ischaemic aetiology HR 1.28 (95% CI 1.21–1.37), P-value for interaction = 0.03. Although there was a trend to worse prognosis in men with ischaemic aetiology, this did not reach statistical significance in either the preserved or reduced EF groups. For patients with non-ischaemic aetiology, men had a higher risk of death from any cause compared with women, in both the preserved and reduced EF groups. The adjusted HR for the different subgroups compared with women with preserved EF and no ischaemic HF is shown in Figure 3B (three-way gender ×EF ×ischaemic aetiology interaction P = 0.0008).
Results
Data were available from 31 studies involving a total of 54 416 patients. Of these, 1179 patients were excluded from the analysis due to irresolvable dates or having died during an index hospital admission, 2246 based on aetiology of HF (either valvular heart disease or hypertrophic cardiomyopathy), 9019 due to missing information on left ventricular EF, and 23 due to missing information on sex. Thus, the main analysis was based on 41 949 patients; 28 052 (67%) men and 13 897 (33%) women.
The baseline characteristics of the study population are shown in Table 1. When compared with men, women were older {70.5 [standard deviation (SD) 12.1] vs. 65.6 [SD 11.6] years}, more commonly had a history of hypertension (49.9% vs. 40.0%), and less commonly had a reduced EF (62.6% vs. 81.6%). Women had more severe functional limitation than men, with a greater proportion of women than men in New York Heart Association (NYHA) class III or IV. Mean heart rate was also higher in women. Overall, women were prescribed angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and beta-blockers less frequently than men. The under-use in women of these treatments was particularly evident in patients with reduced EF (ACE inhibitors or ARBs 79.0% vs. 84.6%; beta-blocker 36.2% vs. 39.7%).
Survival
During 3 years follow-up, 3521 (25.3%) women and 7232 (25.7%) men died. There were 137 [95% confidence interval (CI) 133–140] deaths per 1000 patient-years in men and 135 (95% CI 131–139) deaths per 1000 patient-years in women. On analysis only adjusted for age, men were at higher risk of death than women [hazard ratio (HR) 1.31, 95% CI 1.25–1.36] (Figure 1). As previously reported, on multivariable analysis, male sex showed an independent association with the risk of death at 3 years (HR 1.23, 95% CI 1.18–1.28). When the randomized controlled trials of pharmacotherapy (three trials, 20 878 patients) were excluded from the analysis, the risk of death remained higher among men (fully adjusted HR 1.27, 95% CI 1.19–1.36).
(Enlarge Image)
Figure 1.
All-cause mortality for men and women adjusted for age (P < 0.001).
Age, Left Ventricular Ejection Fraction, and Hypertension
The excess mortality risk associated with male sex was of similar magnitude in patients with reduced or preserved EF (Figure 2). Neither age (P = 0.63) nor history of hypertension (P = 0.10) altered the differential relationship between sex and outcome. However, both diabetes (P < 0.001) and aetiology of HF (P = 0.03) did appear to modify this relationship.
(Enlarge Image)
Figure 2.
All-cause mortality for men and women with heart failure and preserved ejection fraction (HF-PEF) or reduced ejection fraction (HF-REF) adjusted for age (EF group × gender interaction P = 0.72).
Diabetes
Diabetes was present more frequently in women (25.4%) than in men (22.8%, P < 0.001). In patients with reduced EF, diabetes was present among 26.6% of women and 23.1% of men (P < 0.001), and in patients with preserved EF, among 23.6% of women and 21.7% of men (P = 0.03). There were 2997 deaths among 9776 patients (30.7%) with, and 7366 deaths among 31 513 patients (23.4%) without, diabetes. After adjustment for covariates, diabetes retained an independent association with death from any cause (adjusted HR 1.41, 95% CI 1.35–1.47) and with cardiovascular death (HR 1.51, 95% CI 1.41–1.62).
Concomitant diabetes attenuated the lower risk of death associated with female sex (risk of death for men vs. women: diabetes HR 1.11, 95% CI 1.03–1.20; no diabetes 1.37, 95% CI 1.30–1.45, P-value for interaction <0.0001). Diabetes also appeared to modify the relationship between sex and mortality, irrespective of left ventricular EF. Among patients with diabetes, there was no statistically significant difference in the HR for death from any cause between men and women in either the preserved or reduced EF groups. However, for patients without diabetes, men had a higher risk of death from any cause compared with women, in both the preserved and reduced EF groups. The adjusted HR for different subgroups, with women with preserved EF and no diabetes as the comparator, is shown in Figure 3A. The three-way interaction for gender ×EF ×diabetes was not statistically significant (P = 0.208).
(Enlarge Image)
Figure 3.
(A) Risk of death of heart failure (HF) patients by sex, diabetes mellitus (DM), and ejection fraction group (preserved HF-PEF or reduced HF-REF) adjusted for age and stratified by study (gender × EF group × diabetes interaction P = 0.208). (B) Risk of death of HF patients by sex, aetiology, and ejection fraction group (HF-PEF or HF-REF) adjusted for age and stratified by study (gender × EF group × ischaemic aetiology interaction P = 0.0008). CI, confidence interval.
Aetiology
Ischaemic aetiology was less frequent among women (46.3%) than men (58.7%, P < 0.001). Ischaemic aetiology was recorded in 61.4% of men and 50.9% of women (P < 0.001) with reduced EF, and in 46.9% of men and 38.6% of women (P < 0.001) with preserved EF. Ischaemic aetiology showed an independent association with death from any cause (adjusted HR 1.07, 95% CI 1.03–1.12), and cardiovascular death (HR 1.11, 95% CI 1.04–1.19).
The aetiology of HF appeared to modify the association between sex and outcome: risk of death for men vs. women with ischaemic HF, adjusted HR 1.17 (95% CI 1.10–1.24); non-ischaemic aetiology HR 1.28 (95% CI 1.21–1.37), P-value for interaction = 0.03. Although there was a trend to worse prognosis in men with ischaemic aetiology, this did not reach statistical significance in either the preserved or reduced EF groups. For patients with non-ischaemic aetiology, men had a higher risk of death from any cause compared with women, in both the preserved and reduced EF groups. The adjusted HR for the different subgroups compared with women with preserved EF and no ischaemic HF is shown in Figure 3B (three-way gender ×EF ×ischaemic aetiology interaction P = 0.0008).
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