Heart Failure in Younger Patients
Thirty-one studies contributed data on 41 926 patients whose baseline characteristics are presented in Table 1. The relative proportion of women increased with age (29% <40, 22% 40–49, 23% 50–59, 27% 60–69, 38% 70–79, and 52% ≥80 years; P < 0.0001).
Younger patients had the lowest prevalence of comorbidities (<40 vs. ≥80 years: hypertension 22 vs. 43%, P < 0.0001; MI 14 vs. 35%, P = 0.019; AF 9 vs. 30%, P < 0.0001; and diabetes 9 vs. 18%, P < 0.0001; Table 1). The prevalence of comorbidities increased with age.
The aetiology of HF varied with age. Since the term 'idiopathic' may refer to dilated cardiomyopathy (typically inferring reduced EF), aetiology was examined separately in the overall population and those with HF-REF (Table 1). In both cohorts, the youngest age group had the highest proportion of 'idiopathic' cardiomyopathy, which declined sharply >40 years of age (overall 63% <40 years, 37% 40–49 years, 28% 50–59 years, 20% 60–69 years, 12% 70–79, and 7% ≥80 years; P < 0.001). This reflected converse parallel trends in the proportion of patients with ischaemic and hypertensive aetiology, which both increased with age: aetiology presumed to be ischaemic increased from 16% in those aged <40 to 68% in those aged ≥80 years (P < 0.0001); hypertensive from 5% <40 to17% ≥80 years (P = 0.18). The proportion of HF attributed to alcohol was low in all age categories, ranging from 0 to 4%.
The median EF was lowest in the youngest and progressively increased with age (31% <40, 33% 40–49, 33% 50–59, 34% 60–69, 37% 70–79, and 42% ≥80 years; P < 0.0001). The proportion of patients with HF-PEF (LVEF ≥50%) trebled from the youngest to oldest age groups: 14% in <40 years of age to 39% in those age ≥ 80 (P < 0.0001; Table 1).
Younger patients were predominantly in NYHA functional class I or II. The proportion of patients in NYHA functional classes III and IV increased with age. The mean systolic blood pressure was lowest in the youngest age group (118 ± 19 mmHg < 40 years vs. 137 ± 26 mmHg ≥80 years; P < 0.0001). Younger patients were more likely to receive disease-modifying medical therapies, including an ACEI or ARB, a beta-blocker, and spironolactone. Younger patients were also more often treated with digoxin, despite their much lower prevalence of atrial fibrillation. Excluding the DIG trial from the analysis, similar patterns were observed. In contrast, younger patients were less likely to receive diuretics (70% <40 years vs. 85% ≥80 years; P < 0.0001).
During 3-year follow-up, 10 747 patients died. Deaths per 1000 patient-years increased with age from 64 (95% CI: 53–78) in the youngest age group to 276 (95% CI: 266–287) in the oldest age group. Likewise, the probability of death was lowest in the youngest age group and increased with age (Table 2). The estimated 3-year cumulative mortality was 16.5% <40, 16.2% 40–49, 18.2% 50–59, 26.2% 60–69, 37.5% 70–79, and 57.2% ≥80 years (Table 2). There was no significant age–sex interaction for all-cause mortality. The mortality rates in younger patients with HF-PEF were half those of patients with HF-REF [deaths per 1000 patient-years: HF-PEF vs. HF-REF: 19.3 vs. 70.9 in <40 years, 31.7 vs. 68.9 in 40–49 years, and 42.1 vs. 80.0 in 50–59 years (see Supplementary material online, Table S1)]. The deaths per 1000 patient-years were similar for patients in the randomized controlled trials (RCTs) compared with those in the observational studies (see Supplementary material online, Table S1).
After adjusting for sex, ischaemic aetiology, diabetes, hypertension, and atrial fibrillation, mortality remained lowest in the youngest patients (<60 years) in patients with both HF-REF and HF-PEF (Figure 1A and B). The hazard ratio for all-cause mortality increased with increasing age (compared with age 50–59 years as the reference group), and was lowest in those aged <60 years (Figure 2). The hazard ratios for the three youngest age groups (<40 years, 40–49, and 50–59 years) did not differ significantly. A sensitivity analysis incorporating NYHA class, ACEI, ARB, and beta-blocker did not alter the association between age and outcomes.
(Enlarge Image)
Figure 1.
Mortality curves adjusted for sex, ischaemic aetiology, diabetes, hypertension, and atrial fibrillation stratified by age for (A) heart failure with reduced left ventricular ejection fraction and (B) heart failure with preserved left ventricular ejection fraction.
(Enlarge Image)
Figure 2.
Adjusted hazard ratios for all-cause mortality by age categories, with 50–59 years as the reference group. (A) Heart failure with reduced left ventricular ejection fraction. (B) Heart failure with preserved left ventricular ejection fraction.
Results
Demography
Thirty-one studies contributed data on 41 926 patients whose baseline characteristics are presented in Table 1. The relative proportion of women increased with age (29% <40, 22% 40–49, 23% 50–59, 27% 60–69, 38% 70–79, and 52% ≥80 years; P < 0.0001).
Comorbidities
Younger patients had the lowest prevalence of comorbidities (<40 vs. ≥80 years: hypertension 22 vs. 43%, P < 0.0001; MI 14 vs. 35%, P = 0.019; AF 9 vs. 30%, P < 0.0001; and diabetes 9 vs. 18%, P < 0.0001; Table 1). The prevalence of comorbidities increased with age.
Aetiology
The aetiology of HF varied with age. Since the term 'idiopathic' may refer to dilated cardiomyopathy (typically inferring reduced EF), aetiology was examined separately in the overall population and those with HF-REF (Table 1). In both cohorts, the youngest age group had the highest proportion of 'idiopathic' cardiomyopathy, which declined sharply >40 years of age (overall 63% <40 years, 37% 40–49 years, 28% 50–59 years, 20% 60–69 years, 12% 70–79, and 7% ≥80 years; P < 0.001). This reflected converse parallel trends in the proportion of patients with ischaemic and hypertensive aetiology, which both increased with age: aetiology presumed to be ischaemic increased from 16% in those aged <40 to 68% in those aged ≥80 years (P < 0.0001); hypertensive from 5% <40 to17% ≥80 years (P = 0.18). The proportion of HF attributed to alcohol was low in all age categories, ranging from 0 to 4%.
Heart Failure With Reduced Left Ventricular Ejection Fraction and Heart Failure With Preserved Left Ventricular Ejection Fraction
The median EF was lowest in the youngest and progressively increased with age (31% <40, 33% 40–49, 33% 50–59, 34% 60–69, 37% 70–79, and 42% ≥80 years; P < 0.0001). The proportion of patients with HF-PEF (LVEF ≥50%) trebled from the youngest to oldest age groups: 14% in <40 years of age to 39% in those age ≥ 80 (P < 0.0001; Table 1).
Clinical Status, Blood Pressure, Heart Rate, and Treatment
Younger patients were predominantly in NYHA functional class I or II. The proportion of patients in NYHA functional classes III and IV increased with age. The mean systolic blood pressure was lowest in the youngest age group (118 ± 19 mmHg < 40 years vs. 137 ± 26 mmHg ≥80 years; P < 0.0001). Younger patients were more likely to receive disease-modifying medical therapies, including an ACEI or ARB, a beta-blocker, and spironolactone. Younger patients were also more often treated with digoxin, despite their much lower prevalence of atrial fibrillation. Excluding the DIG trial from the analysis, similar patterns were observed. In contrast, younger patients were less likely to receive diuretics (70% <40 years vs. 85% ≥80 years; P < 0.0001).
Mortality
During 3-year follow-up, 10 747 patients died. Deaths per 1000 patient-years increased with age from 64 (95% CI: 53–78) in the youngest age group to 276 (95% CI: 266–287) in the oldest age group. Likewise, the probability of death was lowest in the youngest age group and increased with age (Table 2). The estimated 3-year cumulative mortality was 16.5% <40, 16.2% 40–49, 18.2% 50–59, 26.2% 60–69, 37.5% 70–79, and 57.2% ≥80 years (Table 2). There was no significant age–sex interaction for all-cause mortality. The mortality rates in younger patients with HF-PEF were half those of patients with HF-REF [deaths per 1000 patient-years: HF-PEF vs. HF-REF: 19.3 vs. 70.9 in <40 years, 31.7 vs. 68.9 in 40–49 years, and 42.1 vs. 80.0 in 50–59 years (see Supplementary material online, Table S1)]. The deaths per 1000 patient-years were similar for patients in the randomized controlled trials (RCTs) compared with those in the observational studies (see Supplementary material online, Table S1).
After adjusting for sex, ischaemic aetiology, diabetes, hypertension, and atrial fibrillation, mortality remained lowest in the youngest patients (<60 years) in patients with both HF-REF and HF-PEF (Figure 1A and B). The hazard ratio for all-cause mortality increased with increasing age (compared with age 50–59 years as the reference group), and was lowest in those aged <60 years (Figure 2). The hazard ratios for the three youngest age groups (<40 years, 40–49, and 50–59 years) did not differ significantly. A sensitivity analysis incorporating NYHA class, ACEI, ARB, and beta-blocker did not alter the association between age and outcomes.
(Enlarge Image)
Figure 1.
Mortality curves adjusted for sex, ischaemic aetiology, diabetes, hypertension, and atrial fibrillation stratified by age for (A) heart failure with reduced left ventricular ejection fraction and (B) heart failure with preserved left ventricular ejection fraction.
(Enlarge Image)
Figure 2.
Adjusted hazard ratios for all-cause mortality by age categories, with 50–59 years as the reference group. (A) Heart failure with reduced left ventricular ejection fraction. (B) Heart failure with preserved left ventricular ejection fraction.
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