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The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure
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Original article
The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure Ayaka Nozaki (MD)a, Akihiro Shirakabe (MD, PhD)b,*, Noritake Hata (MD, PhD)b, Nobuaki Kobayashi (MD, PhD)b, Hirotake Okazaki (MD, PhD)b, Masato Matsushita (MD)b, Yusaku Shibata (MD)b, Suguru Nishigoori (MD)b, Saori Uchiyama (MD)b, Yoshiki Kusama (MD, PhD, FJCC)a, Kuniya Asai (MD, PhD)c, Wataru Shimizu (MD, FJCC)c a b c
Department of Cardiovascular Medicine, Nippon Medical School Tama Nagayama Hospital, Tokyo, Japan Division of Intensive Care Unit, Chiba Hokusoh Hospital, Nippon Medical School, Chiba, Japan Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 23 September 2016 Received in revised form 13 November 2016 Accepted 30 November 2016 Available online xxx
Background: The gender differences in the prognosis of Asian patients with acute heart failure (AHF) remain to be elucidated. Methods and results: One thousand fifty AHF patients were enrolled. The patients were assigned to a female group (n = 354) and a male group (n = 696). A Kaplan–Meier curve showed that the cardiovascular survival rate of the female group was significantly lower than that of the male group (p = 0.005). A multivariate Cox regression model identified female gender [hazard ratio (HR): 1.381, 95% CI: 1.018–1.872] as an independent predictor of 730-day cardiovascular death. In subgroup analysis by age, in patients over 79 years, female gender significantly increased the cardiovascular death (HR: 1.715, 95% CI: 1.088–2.074, p < 0.001) with a significant interaction (p-value for interaction < 0.001). The prognosis, including cardiovascular death, was significantly poorer among elderly female patients (79 years) than among elderly male patients (p = 0.019). The multivariate Cox regression model identified female gender as an independent predictor of 730-day cardiovascular death in patients who were older than 79 years of age (HR, 1.943; 95% CI, 1.192–3.167). Conclusions: Female gender was associated with poor prognosis in AHF patients. In particular, old age (79 years) was associated with adverse outcomes in female patients with AHF. ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Sex Age Preserved ejection fraction Acute heart failure syndrome
Introduction Some epidemiological studies have demonstrated gender differences in cardiovascular disease. Women with acute coronary syndrome are reported to be older and are more likely to have hypertension, dyslipidemia, and diabetes, and to have poor outcomes, including worse in-hospital mortality and long-term prognoses [1–4]. Meanwhile, other studies have suggested that there are no gender differences in acute coronary syndrome [5]. Cardiovascular disorders, including acute coronary syndrome, sometimes induce heart failure (HF). HF is therefore a major and
* Corresponding author at: ICU, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba 270-1694, Japan. Fax: +81 476 99 1911. E-mail address: [email protected] (A. Shirakabe).
increasing problem in the cardiovascular field. Gender differences have been demonstrated in patients with chronic HF or acute HF (AHF), with women reported to have a better prognosis than men [6–9], while other studies reported that there were no differences in the prognoses of male and female patients [10–13]. These HF studies included lower numbers of female patients than male patients, and the female HF patients were characterized as being older and having a non-ischemic and valvular etiology, a preserved left ventricular ejection fraction (LVEF), and a maintained renal function. AHF syndrome is currently defined, according to the European Society of Cardiology guidelines, as sudden life-threatening severely decompensated (HF) [14], and some investigators reported predictive factors for worse outcomes [15–17]. However, gender differences have not been evaluated in detail in AHF registries of Asian patients – in particular, in Japanese
http://dx.doi.org/10.1016/j.jjcc.2016.11.015 0914-5087/ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015
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patients [18–20]. Furthermore, the prognostic impact of gender, especially the relationship between gender and age, has not been elucidated in Asian AHF patients. We therefore investigated the gender differences in the characteristics and the prognosis of severely decompensated AHF patients who were admitted to an intensive care unit (ICU). Methods Subjects One thousand fifty AHF patients who were admitted to the ICU in Nippon Medical School Chiba Hokusoh Hospital between January 2000 and September 2014 were analyzed in the present study. All of the patients had a New York Heart Association (NYHA) functional class of either III or IV. The treating physician in the emergency department diagnosed AHF within 30 min of admission (based on these criteria) by filling out a form. AHF was defined as either new-onset HF or the decompensation of chronic HF with symptoms that were sufficient to warrant hospitalization [21]. HF was diagnosed according to the Framingham criteria for clinical HF, based on the patient fulfilling 2 major criteria or 1 major criterion and 2 minor criteria [22]. Patients with HF caused by acute coronary syndrome were excluded from this study. The patients who met one of the following criteria were admitted to the ICU: (1) patients who required high projectile oxygen inhalation (including mechanical support) to treat orthopnea; (2) patients who required inotrope or mechanical support due to low blood pressure; and (3) patients who required various types of diuretics to improve general or lung edema. All of the patients in the present study received either intravenous diuretics or vasodilators for the treatment of AHF after admission. The data were retrospectively reviewed from the patients’ hospital medical records.
Statistical analysis All of the statistical analyses were performed using the SPSS 22.0 software program (SPSS Japan Institute, Tokyo, Japan). All of the numerical data were expressed as the median and range or the median and the 25–75% interquartile range, depending on normality. Normality was assessed using the Shapiro–Wilk W test. The Mann–Whitney U-test and Kruskal–Wallis test were used for comparisons between two or more groups. The chi-squared test was used to compare proportions. Values of p < 0.05 were considered to indicate statistical significance. The prognostic value in terms of 730-day cardiovascular mortality was evaluated using a Cox regression hazard model and a Kaplan–Meier curve. All clinically relevant factors affecting the prognosis, including gender, age (per 1 year increase), SBP (per 10 mmHg increase), heart rate (per 1 bpm increase), serum creatinine level (per 0.1 mg/dl increase), total bilirubin (per 1.0 mmol/L increase), sodium (per 1.0 mmol/L increase), CRP (per 1.0 mg/dl increase), hemoglobin (per 1.0 mg/dl increase), and LVEF (per 10% increase) were selected for inclusion in the multivariate Cox regression hazard model associated with 730 days cardiovascular death in all patients cohort. Multivariate Cox regression hazard model was performed by the backward stepwise selection. We also conducted a subgroup analysis stratified by age (<79 years and 79 years), LVEF (<41% and 41%), type of HF (de novo and re-admission), etiology (valvular disease and nonvalvular disease), hemoglobin (12.4 g/dl and >12.4 g/dl), and creatinine (1.0 mg/dl and >1.0 mg/dl) with a formal interaction test between each group and the risk of female relative to male. The continuous variables were dichotomized by median values of female. Furthermore, the multivariate Cox regression hazard model and Kaplan–Meier curve analysis were performed again in age category (<79 years, 79 years). Ethics review
Procedures The patients were divided into female (n = 354) and male (n = 696) groups. We compared the patients’ characteristics, including their age, the presence of de novo or recurrent HF, the etiology of HF, the risk factors for atherosclerosis (diabetes mellitus, hypertension, and dyslipidemia), vital signs [systolic blood pressure (SBP) and heart rate], arterial blood gas, the LVEF on echocardiograms, laboratory data [blood urea nitrogen (BUN), total bilirubin, hemoglobin, brain natriuretic peptide (BNP), C-reactive protein (CRP) and other variables], the medications that were administered during their admission to the ICU and the short-term prognosis (the duration of ICU stay, hospital stay, and in-hospital mortality). The LVEF was calculated using the Teichholz method or modified Simpson’s method on admission (Sonos 5500, Hewlett Packard, Palo Alto, CA, USA or Vivid I, GE Yokogawa Medical, Tokyo, Japan). The evaluation of LVEF was performed at emergency department on admission. Prognosis The long-term prognosis, including cardiovascular death within 730 days, was evaluated. Cardiovascular death was defined as cardiac death, sudden death, cerebrovascular death, and HF death. The patients were followed-up at a routine outpatient clinic. The prognosis of the patients who were followed-up at other institutes was determined by telephone contact. The prognostic value in terms of 730-day cardiovascular mortality was evaluated using a Cox regression hazard model and a Kaplan– Meier curve.
The institutional review board of Nippon Medical School Chiba Hokusoh Hospital approved the study protocol. Results The patient characteristics and the prognosis in the female and male patients Female patients comprised 33.7% of the study population. The median age was 74 years and the median LVEF was 35%; 354 (33.7%) patients had re-admission HF, and 846 (80.6%) patients had NHYA class IV on admission. Table 1 shows the characteristics (on admission) of the patients in the two groups. The female patients were significantly older than the male patients. In comparison to the male patients, the female patients were less likely to be re-admitted for HF and their LVEF was significantly preserved. The female patients were less likely to have ischemic heart disease and valvular disease was more likely to be the etiology of their HF. There were no significant differences in the history or in the arterial blood gas data of the two groups. The female patients showed significantly lower serum levels of uric acid, hemoglobin, creatinine, and CRP. There were no significant differences between the two groups regarding the length of ICU hospitalization and total hospitalization, or the in-hospital mortality rate. Median follow-up date for long-term prognosis was 556 days in the overall population. All-cause deaths occurred in 225 patients (22.4%), and cardiovascular deaths occurred in 203 patients (19.3%) of the 1020 patients within 730 days. In 825 survival patients, 463 patients (56.1%) were followed-up for 730 days.
Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015
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Table 1 The patients’ characteristics. Characteristic Status and vital signs Age (years old) Type (re-admission, %) NYHA (IV, %) LVEF (%) Systolic blood pressure (mmHg) Pulse (beats/min) Past medical history Ischemia (yes, %) Hypertensive heart disease (yes, %) Cardiomyophathy (yes, %) Valvular disease (yes, %) Others (yes, %) Past medical history Hypertension (yes, %) Diabetes mellitus (yes, %) Dyslipidemia (yes, %) Arterial blood gas pH pCO2 (mmHg) pO2 (mmHg) HCO3 (mmol/L) SaO2 (%) Lactate (mmol/L) Laboratory data Total bilirubin (mg/dl) Uric acid (mg/dl) Sodium (mmol/L) Potassium (mmol/L) Hemoglobin (g/dl) BUN (mmol/L) Creatinine (g/dl) CRP (mg/dl) BNP (pg/ml) Medication (cases) during ICU Furosemide (yes, %) Nitroglycerin (yes, %) Nicorandil (yes, %) Carperitide (yes, %) Dopamine (yes, %) Dobutamine (yes, %) ACE-I/ARB (yes, %) b-Blocker (yes, %) Spironolactone (yes, %) Outcome ICU hospitalization (days) Total hospitalization (days) In-hospital mortality (yes, %)
Total (n = 1050)
Female (n = 354)
Male (n = 696)
p-Value
74 (65–81) 354 (33.7%) 846 (80.6%) 35 (25–49) 160 (130–183) 112 (93–130)
79 (70–85) 97 (27.4%) 281 (79.4%) 41 (30–56) 155 (129–180) 112 (92–130)
72 (64–78) 257 (36.9%) 565 (81.2%) 32 (23–44) 160 (130–186) 112 (93–130)
<0.001 0.002 0.510 <0.001 0.072 0.977
440 (42.0%) 168 (16.0%) 130 (12.4%) 237 (22.6%) 71 (6.8%)
107 (30.2%) 55 (15.5%) 25 (7.1%) 132 (37.3%) 32 (9.0%)
333 (47.8%) 113 (16.2%) 105 (15.1%) 105 (15.1%) 39 (5.6%)
<0.001 0.790 <0.001 <0.001 0.038
760 (72.4%) 459 (43.7%) 473 (45.0%)
262 (74.0%) 151 (42.7%) 152 (42.9%)
498 (71.6%) 308 (44.3%) 321 (46.1%)
0.422 0.645 0.348
7.33 (7.20–7.42) 42.5 (33.7–55.8) 88 (66–133) 22 (19–24) 96 (90–98) 1.7 (1.1–3.4)
7.33 (7.22–7.41) 44.0 (34.7–55.0) 92 (67–145) 22 (20–25) 96 (91–98) 1.7 (1.1–3.5)
7.33 (7.19–7.43) 41.7 (33.3–56.7) 86 (65–130) 22 (19–24) 96 (89–98) 1.8 (1.2–3.4)
0.671 0.233 0.151 0.259 0.210 0.571
0.6 (0.4–0.9) 6.8 (5.3–8.1) 140 (137–142) 4.2 (3.9–4.7) 12.4 (10.6–14.2) 23.8 (17.9–34.6) 1.18 (0.90–1.77) 0.64 (0.20–2.22) 785 (418–1399)
0.6 (0.4–0.8) 6.2 (4.8–7.6) 140 (137–142) 4.2 (3.8–4.7) 11.4 (10.1–12.7) 23.3 (17.3–33.0) 1.00 (0.78–1.41) 0.53 (0.17–1.78) 851 (394–1572)
0.6 (0.4–0.9) 7.0 (5.7–8.3) 140 (137–142) 4.3 (3.9–4.7) 12.9 (11.0–14.9) 24.1 (18.1–36.5) 1.32 (1.00–1.88) 0.68 (0.21–2.49) 736 (425–1340)
0.051 <0.001 0.449 0.096 <0.001 0.122 <0.001 0.060 0.356
986 695 155 555 259 228 405 260 371
(93.9%) (66.2%) (14.8%) (52.9%) (24.7%) (21.7%) (38.6%) (24.7%) (35.3%)
332 (93.8%) 233 (65.8%) 41 (11.6%) 166 (46.9%) 76 (21.5%) 59 (16.7%) 132 (37.3%) 65 (18.4%) 127 (35.9%)
654 462 114 389 183 169 273 195 244
(93.9%) (66.4%) (16.4%) (55.9%) (26.3%) (24.3%) (39.2%) (28.0%) (35.1%)
0.892 0.890 0.043 0.006 0.096 0.004 0.547 0.001 0.838
4 (3–7) 28 (17–46) 107 (10.2%)
4 (3–7) 29 (18–52) 43 (12.1%)
5 (3–7) 27 (17–45) 64 (9.2%)
0.360 0.151 0.160
NYHA, New York Heart Association; LVEF, left ventricular ejection fraction measured by echocardiography; BUN, blood urea nitrogen; CRP, C-reactive protein; BNP, brain natriuretic peptide; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ICU, intensive care unit. The p values between females and males were determined using the Mann–Whitney U-test or the x2 test. All numerical data are expressed as the median (25–75% interquartile range).
The Kaplan–Meier curves for the gender differences are shown in Fig. 1. The female patients had a significantly poorer prognosis, and higher rates of cardiovascular cause death. The multivariate Cox regression model identified female gender as an independent predictor of 730-day cardiovascular mortality [hazard ratio (HR), 1.381; 95% CI, 1.018–1.872] (Table 2). In subgroup analysis by significant factors for female including age, LVEF, type of HF, etiology, hemoglobin, and creatinine, in patients over 79 years, female gender significantly increased the cardiovascular death (HR: 1.715, 95% CI: 1.088–2.074) with a significant interaction (p-value for interaction < 0.001). The patients with non-valvular disease also had increased cardiovascular death (HR: 1.616, 95% CI: 1.131–2.304) with a significant interaction (p-value for interaction = 0.010) (Fig. 2). Thus, the higher risk of female relative to male for 730 days cardiovascular death was consistent with the patients over 79 years and with nonvalvular disease. There was significant interaction between the age
and etiology group, and the risk of female relative to male for 730 days cardiovascular death. Older age and a valvular etiology were significant characteristics in female gender, which means that only age was positively associated with female gender among patients with AHF. We paid attention to age factors that were associated with female gender, and performed further evaluations. The prognosis in age category The gender distribution of the AHF patients is shown in Fig. 3. The overall population included 354 (33.7%) female patients and 696 (66.3%) male patients. Among the patients who were over 79 years of age (n = 345), there were 188 (54.5%) female patients. Meanwhile, in the patients who were under 79 years of age (n = 705), there were only 166 (23.5%) female patients. The Kaplan–Meier survival curves showed that the prognosis, including cardiovascular cause death, was significantly poorer
Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015
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Overall Population
among the female patients who were 79 years of age than it was in the male patients who were 79 years of age (p = 0.019) (Fig. 4A). In contrast, there was no significant difference between the male and female patients who were <79 years of age (p = 0.836) (Fig. 4B). The multivariate Cox regression model identified female gender as an independent predictor of 730-day cardiovascular mortality among the patients who were 79 years of age (HR, 1.943; 95% CI, 1.192–3.167; p = 0.001), but not in patients <79 years of age (Table 3).
Cumulative survival
1 0.8 0.6
p=0.005
0.4 male (n=696)
0.2
Discussion
female (n=354)
Comparisons with previous studies
0 0
200
400
600
512 226
411 182
351 155
800 days
Number at risk male female
327 138
Fig. 1. The Kaplan–Meier survival curves showed that the rate of all-cause death within 730 days after admission was significantly lower in the female patients (n = 356) than in the male patients (n = 701).
Although there have been several large cohort registries of AHF patients [18–20], little is known about the gender differences in Asian AHF patients. The gender differences in Acute Decompensated Heart Failure Syndromes (ATTEND) Registry, which is the largest registry of hospitalized HF patients in Asian countries [19], have not been investigated in detail. Meanwhile, the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) [23]
Table 2 The multivariate analyses of the associations between 730-day cardiovascular death and the clinical findings. All patients
Univariate
Gender (female) Laboratory data Age (per 1 year increase) SBP (per 10 mmHg increase) Heart rate (per 1 bpm increase) Creatinine (per 0.1 mg/dl increase) Total bilirubin (per 1 mg/dl increase) Sodium (per 1.0 mmol/L increase) CRP (per 1 mg/dl increase) Hemoglobin (per 1.0 mg/dl increase) LVEF (per 10% increase)
HR
95% CI
1.496
1.131–1.98
1.034 0.853 0.990 1.010 1.131 0.937 1.007 1.003 0.997
1.020–1.047 0.822–0.885 0.985–0.994 1.003–1.016 1.047–1.222 0.915–0.959 0.998–1.017 0.993–1.013 0.919–1.082
Multivariate p-Value
HR
95% CI
p-Value
0.005
1.381
1.018–1.872
0.038
<0.001 <0.001 <0.001 0.004 0.002 <0.001 0.126 0.591 0.951
1.032 0.986
1.017–1.047 0.982–0.99
<0.001 <0.001
1.011 1.142 0.962
1.004–1.019 1.037–1.258 0.938–0.985
0.003 0.007 0.002
HR, hazard ratio; CI, confidence interval; SBP, systolic blood pressure; CRP, C-reactive protein; LVEF, left ventricular ejection fraction measured by echocardiography.
p
All Patients
1.496 (1.131-1.980)
Age ≥79 years Age <79 years
1.715 (1.088-2.704)
LVEF ≥41 % LVEF <41 %
1.264 (0.815-1.959) 1.602 (1.103-2.326)
p=0.081
De novo Re-admission
1.341 (0.916-1.964) 2.103 (1.391-3.179)
p=0.050
Valvular disease Non-valvular disease
0.824 (0.514-1.321) 1.616 (1.131-2.304)
p=0.010
Hb ≤ 12.4 g/dl Hb >12.4 g/dl
1.172 (0.800-1.719) 1.441 (0.922-2.158)
p=0.717
Creatinine ≤ 1.0 mg/dl Creatinine >1.0 mg/dl
2.535 (1.326-4.845) 1.704 (1.223-2.343)
p=0.423
male worse
1.046 (0.685-1.596)
0
1
2
3
4
5
interaction
p<0.001
Female worse
Fig. 2. Forest plot of hazard ratios by patient subgroups for cardiovascular death. Female gender significantly increased cardiovascular death (HR: 1.715, 95% CI: 1.088–2.074) with a significant interaction (p-value for interaction < 0.001). The patients with non-valvular disease increased cardiovascular death (HR: 1.616, 95% CI: 1.131–2.304) with a significant interaction (p-value for interaction = 0.010).
Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015
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female HF patients showed better survival [25]; however, some recent analyses have suggested that male and female patients show similar outcomes [7,8,11,13,26]. It has been reported that gender differences of HF patients may be affected by race [8]. It is therefore important to evaluate the gender differences in Asian patients, especially in Japanese patients. Furthermore, the previous studies included a relatively high percentage of female AHF patients (42–52%); in contrast, 33.7% of the patients in the present study were female [18,19,27]. Thus, there might be several definitive differences between the cohort of the present study and the cohorts of previous studies that investigated the gender of HF patients. The present study reveals the prognostic impact of gender in Japanese patients who were emergently hospitalized due to AHF, and suggests that female patients showed a worse outcome.
250 Number of Patients
5
200
150
100
50
Age, LVEF, and the prognoses of female and male AHF patients
0 ≤40
40-49
50-59
60-69
70-79
80-89
≥90
age Fig. 3. The distribution of the age of the AHF patients. The blue bar shows the male patients; the red bar shows the female patients. There were 1050 AHF patients in the study. Among the patients who were 79 years of age (n = 345), there were 188 female patients (54.5%) and 157 male patients (45.5%). Among the patients who were <79 years of age (n = 705), there were 166 female patients (23.5%) and 539 male patients (76.5%). AHF, acute heart failure.
and Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-2 [9] suggested that female patients with chronic HF were older, and had a lower prevalence of ischemic heart disease, diabetes, smoking, and myocardial infarction. Moreover, female patients with chronic HF had better survival after adjustment for baseline differences [9]. However, these studies only included patients with chronic HF and excluded patients with AHF [24]. The pathophysiology of AHF is considered different from that of chronic HF. Thus, the implications of gender in each condition in Asian individuals, in particular Japanese individuals, might also be different. All of the subjects in the present study were Japanese. Although some previous reports have focused on patients with acute or advanced decompensated HF [7,8,11,13,25,26], all of the subjects in those studies were non-Japanese. Earlier studies suggest that
(A)
Age
Our present study suggested that female AHF patients are characterized by older age, de novo HF, a preserved LVEF, valvular disease, non-cardiomyopathy, non-ischemic heart disease, and low uric acid, hemoglobin, and creatinine levels. Furthermore, female AHF patients were less likely to use a vasodilator (i.e. niconrandil or carperitide) and were less likely to use inotropes (i.e. dobutamine). Female gender was associated with a poorer prognosis, especially among older patients. Older age was a significant interaction with female gender in the AHF patients of the present study. Thus, a higher percentage of the older AHF patients were female. Although the precise reason for this is unclear, previous studies have suggested some hypotheses. First, an etiological issue could be involved. It has been reported that ischemic heart disease frequently develops in middle-aged men and elderly women, and more frequently develops in men than in women [1–4]. In fact, few of the female patients in the present study had ischemic AHF. Valvular disease, such as aortic stenosis, mitral regurgitation or combined valvular disease generally induces HF in elderly patients. These etiological findings might be one reason why older age was associated with AHF. Second, the younger age group included an increased number of male AHF patients. Thus, the patients tended to die earlier and were thus less likely to reach older age. Furthermore, the average life span of men is shorter than that of women; thus, the proportion
(B)
79 years
1 Cumulative survival
Cumulative events
1
Age < 79 years
0.8 0.6 p=0.019
0.4
male (n=157) 0.2
female (n=188)
0
0.8 0.6 p=0.836
0.4
male (n=539) 0.2
female (n=166)
0 0
Number at risk male female
200 101 109
400 72 77
600 48 61
800 44 54
0
200
400
600
Number at risk male female
412 118
340 102
303 95
800 283 85
Fig. 4. Kaplan–Meier curves in each age category. (A) The Kaplan–Meier survival curves show that the prognosis (including cardiovascular death within 730 days) of the female patients was significantly poorer than that of the male patients. (B) The Kaplan–Meier survival curves show that the prognosis (including cardiovascular death within 730 days) of the male and female patients did not differ to a statistically significant extent.
Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015
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Table 3 The multivariate analyses of the associations between 730-day cardiovascular death and the clinical findings in each category. Age <79 years
Gender (female) Laboratory data Age (per 1 year increase) SBP (per 10 mmHg increase) Heart rate (per 1 bpm increase) Creatinine (per 0.1 mg/dl increase) Total bilirubin (per 1 mg/dl increase) Sodium (per 1.0 mmol/L increase) CRP (per 1 mg/dl increase) Hemoglobin (per 1.0 mg/dl increase) LVEF (per 10% increase)
Univariate HR
95% CI
1.046
0.685–1.596
0.836
1.031 0.822 0.987 1.011 1.150 0.926 1.008 1.004 0.995
1.008–1.054 0.786–0.860 0.981–0.993 1.004–1.019 1.063–1.243 0.902–0.951 0.998–1.018 0.996–1.012 0.891–1.111
Age 79 years
Gender (female) Laboratory data Age (per 1 year increase) SBP (per 10 mmHg increase) Heart rate (per 1 bpm increase) Creatinine (per 0.1 mg/dl increase) Total bilirubin (per 1 mg/dl increase) Sodium (per 1.0 mmol/L increase) CRP (per 1 mg/dl increase) Hemoglobin (per 1.0 mg/dl increase) LVEF (per 10% increase)
Multivariate p-Value
HR
95% CI
p-Value
0.007 0.822 <0.001 0.004 <0.001 <0.001 0.126 0.304 0.928
1.036 0.984
1.012–1.061 0.979–0.988
0.003 <0.001
1.009 1.133 0.959
1.000–1.017 1.020–1.258 0.931–0.988
0.040 0.020 0.006
p-Value
HR
95% CI
1.943
1.192–3.167
0.001
0.992
0.984–0.999
0.030
0.855
0.741–0.987
0.033
Univariate
Multivariate
HR
95% CI
1.715
1.088–2.704
0.020
1.062 0.919 0.996 1.008 1.110 0.961 1.012 0.964 0.994
1.009–1.118 0.860–0.982 0.989–1.003 0.993–1.023 0.717–1.717 0.921–1.002 0.974–1.052 0.878–1.058 0.981–1.006
0.021 0.012 0.226 0.295 0.640 0.062 0.548 0.442 0.330
p-Value
HR, hazard ratio; CI, confidence interval; SBP, systolic blood pressure; CRP, C-reactive protein; LVEF, left ventricular ejection fraction measured by echocardiography.
of female HF patients in the older age group can be expected to increase. There might be a pathophysiological reason for the poorer outcomes of female AHF patients that were observed in the older age group in the present study. The left ventricular geometry indicated by left ventricular end-diastolic pressure and LVEF was also important for HF patients [28]. Women show greater increases in ventricular and arterial stiffness with age, and have a greater adipose mass than men, which also influences the left ventricular geometry to a greater extent than in men [29,30]. It has also been suggested that women develop increased concentric left ventricular remodeling and less ventricular dilation in response to chronic arterial hypertension in comparison to men [31]. Women can therefore be expected to develop HF year by year. Given that the extent of concentric ventricular remodeling is increased in women, and the possibility that this might be associated with a greater loss of diastolic function in the heart of the elderly at the same generation in elderly age, it might be responsible for the worse outcomes in female patients with AHF. We also found that women showed higher LVEF values, and that the outcomes of female patients with a reduced LVEF were poorer in comparison to men with a reduced LVEF. Although the data detail was not shown in the present study, prognostic impact regarding LVEF and gender would be an important issue and should be discussed. Females accounted for a higher proportion of the study population in some previous studies of HF patients with preserved EF values [12,26]. The results of the present study were consistent with this finding. One possible reason could be genderbased differences in the etiologies of AHF. Thus, the LVEF was generally preserved in the patients with valvular disease. Furthermore, some studies have shown that female HF patients with a preserved LVEF may be more sensitive than male patients to cardiac remodeling due to pressure overload [11,32]; another study suggests that reactive oxygen species are more easily produced in women [33]. These molecular findings might explain why AHF developed in different percentages of men and women, even when they showed the same LVEF values.
Previous studies have shown that male and female patients with reduced and preserved EF values have similar rates of inhospital mortality and long-term outcomes [10,12]. Furthermore, Zsilinszka et al. examined sex differences in AHF patients with a preserved LVEF who were admitted to an emergency department and concluded that male and female patients showed similar 30day and 180-day mortalities [26]. In the present study, however, the prognosis of female patients was poorer among the group of patients with a reduced LVEF. Although the reason for this finding is unclear, many clinical trials for HF patients with a reduced LVEF have shown that women are less likely to have coronary artery disease as an underlying risk factor and they are more likely to have hypertension [8]. Male AHF patients with a reduced LVEF might be categorized as having ischemic heart disease, while female patients might be categorized as having non-ischemic heart disease (such as dilated cardiomyopathy, the dilated phase of hypertensive heart disease, and end-stage valvular disease). The poor prognosis of female patients with a reduced LVEF might be explained by these etiological characteristics. Overall, the findings suggest the presence of a reciprocal relationship between age and LVEF. As HF patients become older, the population of HF patients with a preserved LVEF would increase. Due to the widespread primary prevention of ischemic heart disease, which causes a reduced LVEF, the incidence of ischemic heart disease would become lower. In the future, the baseline characteristics of AHF might change and the prevalence of female patients might become similar; thus, in the near future, most AHF patients may have a preserved LVEF. There are currently no therapeutic guidelines regarding genderbased treatments. A previous study of hospitalized chronic HF patients revealed that women were equally likely to receive diuretics, but less likely to receive vasodilators or to be treated with evidence-based therapy than men [11]. Early management with intravenous therapeutic agents is reported to be important, and to be associated with a modestly high risk of in-hospital mortality and a longer length of hospital stay in emergently
Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015
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hospitalized AHF patients (particularly older patients) [34]. A gender analysis of the ADHERE registry showed that women were less likely to receive vasodilators and procedure-oriented therapy [11]. In our analysis, we also found that women with AHF were hesitant to receive vasodilators or inotropes such as nocorandil, carperitide, and dobutamine; this might have led to adverse outcomes in our present female cohort. Aggressive treatment in the early phase of AHF might be needed to improve the prognosis of female AHF patients in the emergency department. Study limitations The present study is associated with several limitations that should be considered when interpreting the results. First, the study was performed at a single center and was not a prospective randomized controlled trial. It is therefore possible that unmeasured variables, which might have affected the results, were present. Second, our study population was limited to patients who were admitted to the ICU; AHF patients who were admitted to general wards were excluded from this study. Nonetheless, the majority of patients with severely decompensated AHF were admitted to a ‘‘closed ICU’’ and treated by cardiologists in our institute. Thus, the majority of patients with severely decompensated AHF were admitted to the ICU. In fact, the characteristics of the patients in the present study were similar to those of another prominent Japanese registry study. Third, 4 patients with missing LVEF data (female, n = 2; male, n = 2) were included in the present study. Finally, we could not include the factors from the compensated phase in the multivariate analysis. The medications used, treatments, and other factors in the compensated phase might be additional variables that can be used for predicting the prognosis in both genders. Conclusion Female gender was an independent predictor of the prognosis of patients who were emergently hospitalized for AHF. The female patients were typically elderly and had a preserved LVEF, de novo HF, and valvular disease. In particular, elderly age was associated with adverse outcomes in female patients with AHF. Funding sources This research received no grants from any funding agency in the public, commercial, or not-for-profit sectors. Conflict of interest The authors declare no conflicts of interest in association with the present study. Acknowledgments We are grateful to the staff of the ICU and the medical records office at Nippon Medical School Chiba Hokusoh Hospital for collecting the medical data. References [1] Lee CY, Hairi NN, Wan Ahmad WA, Ismail O, Liew HB, Zambahari R, Ali RM, Fong AY, Sim KH, NCVD-PCI Investigators. Are there gender differences in coronary artery disease? The Malaysian National Cardiovascular Disease Database – Percutaneous Coronary Intervention (NCVD-PCI) Registry. PLOS ONE 2013;8:e72382. [2] Zhang ZM, Rautaharju PM, Prineas RJ, Rodriguez CJ, Loehr L, Rosamond WD, Kitzman D, Couper D, Soliman EZ. Race and sex differences in the incidence and prognostic significance of silent myocardial infarction in the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2016;133:2141–8.
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Original article
The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure Ayaka Nozaki (MD)a, Akihiro Shirakabe (MD, PhD)b,*, Noritake Hata (MD, PhD)b, Nobuaki Kobayashi (MD, PhD)b, Hirotake Okazaki (MD, PhD)b, Masato Matsushita (MD)b, Yusaku Shibata (MD)b, Suguru Nishigoori (MD)b, Saori Uchiyama (MD)b, Yoshiki Kusama (MD, PhD, FJCC)a, Kuniya Asai (MD, PhD)c, Wataru Shimizu (MD, FJCC)c a b c
Department of Cardiovascular Medicine, Nippon Medical School Tama Nagayama Hospital, Tokyo, Japan Division of Intensive Care Unit, Chiba Hokusoh Hospital, Nippon Medical School, Chiba, Japan Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 23 September 2016 Received in revised form 13 November 2016 Accepted 30 November 2016 Available online xxx
Background: The gender differences in the prognosis of Asian patients with acute heart failure (AHF) remain to be elucidated. Methods and results: One thousand fifty AHF patients were enrolled. The patients were assigned to a female group (n = 354) and a male group (n = 696). A Kaplan–Meier curve showed that the cardiovascular survival rate of the female group was significantly lower than that of the male group (p = 0.005). A multivariate Cox regression model identified female gender [hazard ratio (HR): 1.381, 95% CI: 1.018–1.872] as an independent predictor of 730-day cardiovascular death. In subgroup analysis by age, in patients over 79 years, female gender significantly increased the cardiovascular death (HR: 1.715, 95% CI: 1.088–2.074, p < 0.001) with a significant interaction (p-value for interaction < 0.001). The prognosis, including cardiovascular death, was significantly poorer among elderly female patients (79 years) than among elderly male patients (p = 0.019). The multivariate Cox regression model identified female gender as an independent predictor of 730-day cardiovascular death in patients who were older than 79 years of age (HR, 1.943; 95% CI, 1.192–3.167). Conclusions: Female gender was associated with poor prognosis in AHF patients. In particular, old age (79 years) was associated with adverse outcomes in female patients with AHF. ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Sex Age Preserved ejection fraction Acute heart failure syndrome
Introduction Some epidemiological studies have demonstrated gender differences in cardiovascular disease. Women with acute coronary syndrome are reported to be older and are more likely to have hypertension, dyslipidemia, and diabetes, and to have poor outcomes, including worse in-hospital mortality and long-term prognoses [1–4]. Meanwhile, other studies have suggested that there are no gender differences in acute coronary syndrome [5]. Cardiovascular disorders, including acute coronary syndrome, sometimes induce heart failure (HF). HF is therefore a major and
* Corresponding author at: ICU, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba 270-1694, Japan. Fax: +81 476 99 1911. E-mail address: [email protected] (A. Shirakabe).
increasing problem in the cardiovascular field. Gender differences have been demonstrated in patients with chronic HF or acute HF (AHF), with women reported to have a better prognosis than men [6–9], while other studies reported that there were no differences in the prognoses of male and female patients [10–13]. These HF studies included lower numbers of female patients than male patients, and the female HF patients were characterized as being older and having a non-ischemic and valvular etiology, a preserved left ventricular ejection fraction (LVEF), and a maintained renal function. AHF syndrome is currently defined, according to the European Society of Cardiology guidelines, as sudden life-threatening severely decompensated (HF) [14], and some investigators reported predictive factors for worse outcomes [15–17]. However, gender differences have not been evaluated in detail in AHF registries of Asian patients – in particular, in Japanese
http://dx.doi.org/10.1016/j.jjcc.2016.11.015 0914-5087/ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015
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patients [18–20]. Furthermore, the prognostic impact of gender, especially the relationship between gender and age, has not been elucidated in Asian AHF patients. We therefore investigated the gender differences in the characteristics and the prognosis of severely decompensated AHF patients who were admitted to an intensive care unit (ICU). Methods Subjects One thousand fifty AHF patients who were admitted to the ICU in Nippon Medical School Chiba Hokusoh Hospital between January 2000 and September 2014 were analyzed in the present study. All of the patients had a New York Heart Association (NYHA) functional class of either III or IV. The treating physician in the emergency department diagnosed AHF within 30 min of admission (based on these criteria) by filling out a form. AHF was defined as either new-onset HF or the decompensation of chronic HF with symptoms that were sufficient to warrant hospitalization [21]. HF was diagnosed according to the Framingham criteria for clinical HF, based on the patient fulfilling 2 major criteria or 1 major criterion and 2 minor criteria [22]. Patients with HF caused by acute coronary syndrome were excluded from this study. The patients who met one of the following criteria were admitted to the ICU: (1) patients who required high projectile oxygen inhalation (including mechanical support) to treat orthopnea; (2) patients who required inotrope or mechanical support due to low blood pressure; and (3) patients who required various types of diuretics to improve general or lung edema. All of the patients in the present study received either intravenous diuretics or vasodilators for the treatment of AHF after admission. The data were retrospectively reviewed from the patients’ hospital medical records.
Statistical analysis All of the statistical analyses were performed using the SPSS 22.0 software program (SPSS Japan Institute, Tokyo, Japan). All of the numerical data were expressed as the median and range or the median and the 25–75% interquartile range, depending on normality. Normality was assessed using the Shapiro–Wilk W test. The Mann–Whitney U-test and Kruskal–Wallis test were used for comparisons between two or more groups. The chi-squared test was used to compare proportions. Values of p < 0.05 were considered to indicate statistical significance. The prognostic value in terms of 730-day cardiovascular mortality was evaluated using a Cox regression hazard model and a Kaplan–Meier curve. All clinically relevant factors affecting the prognosis, including gender, age (per 1 year increase), SBP (per 10 mmHg increase), heart rate (per 1 bpm increase), serum creatinine level (per 0.1 mg/dl increase), total bilirubin (per 1.0 mmol/L increase), sodium (per 1.0 mmol/L increase), CRP (per 1.0 mg/dl increase), hemoglobin (per 1.0 mg/dl increase), and LVEF (per 10% increase) were selected for inclusion in the multivariate Cox regression hazard model associated with 730 days cardiovascular death in all patients cohort. Multivariate Cox regression hazard model was performed by the backward stepwise selection. We also conducted a subgroup analysis stratified by age (<79 years and 79 years), LVEF (<41% and 41%), type of HF (de novo and re-admission), etiology (valvular disease and nonvalvular disease), hemoglobin (12.4 g/dl and >12.4 g/dl), and creatinine (1.0 mg/dl and >1.0 mg/dl) with a formal interaction test between each group and the risk of female relative to male. The continuous variables were dichotomized by median values of female. Furthermore, the multivariate Cox regression hazard model and Kaplan–Meier curve analysis were performed again in age category (<79 years, 79 years). Ethics review
Procedures The patients were divided into female (n = 354) and male (n = 696) groups. We compared the patients’ characteristics, including their age, the presence of de novo or recurrent HF, the etiology of HF, the risk factors for atherosclerosis (diabetes mellitus, hypertension, and dyslipidemia), vital signs [systolic blood pressure (SBP) and heart rate], arterial blood gas, the LVEF on echocardiograms, laboratory data [blood urea nitrogen (BUN), total bilirubin, hemoglobin, brain natriuretic peptide (BNP), C-reactive protein (CRP) and other variables], the medications that were administered during their admission to the ICU and the short-term prognosis (the duration of ICU stay, hospital stay, and in-hospital mortality). The LVEF was calculated using the Teichholz method or modified Simpson’s method on admission (Sonos 5500, Hewlett Packard, Palo Alto, CA, USA or Vivid I, GE Yokogawa Medical, Tokyo, Japan). The evaluation of LVEF was performed at emergency department on admission. Prognosis The long-term prognosis, including cardiovascular death within 730 days, was evaluated. Cardiovascular death was defined as cardiac death, sudden death, cerebrovascular death, and HF death. The patients were followed-up at a routine outpatient clinic. The prognosis of the patients who were followed-up at other institutes was determined by telephone contact. The prognostic value in terms of 730-day cardiovascular mortality was evaluated using a Cox regression hazard model and a Kaplan– Meier curve.
The institutional review board of Nippon Medical School Chiba Hokusoh Hospital approved the study protocol. Results The patient characteristics and the prognosis in the female and male patients Female patients comprised 33.7% of the study population. The median age was 74 years and the median LVEF was 35%; 354 (33.7%) patients had re-admission HF, and 846 (80.6%) patients had NHYA class IV on admission. Table 1 shows the characteristics (on admission) of the patients in the two groups. The female patients were significantly older than the male patients. In comparison to the male patients, the female patients were less likely to be re-admitted for HF and their LVEF was significantly preserved. The female patients were less likely to have ischemic heart disease and valvular disease was more likely to be the etiology of their HF. There were no significant differences in the history or in the arterial blood gas data of the two groups. The female patients showed significantly lower serum levels of uric acid, hemoglobin, creatinine, and CRP. There were no significant differences between the two groups regarding the length of ICU hospitalization and total hospitalization, or the in-hospital mortality rate. Median follow-up date for long-term prognosis was 556 days in the overall population. All-cause deaths occurred in 225 patients (22.4%), and cardiovascular deaths occurred in 203 patients (19.3%) of the 1020 patients within 730 days. In 825 survival patients, 463 patients (56.1%) were followed-up for 730 days.
Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015
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3
Table 1 The patients’ characteristics. Characteristic Status and vital signs Age (years old) Type (re-admission, %) NYHA (IV, %) LVEF (%) Systolic blood pressure (mmHg) Pulse (beats/min) Past medical history Ischemia (yes, %) Hypertensive heart disease (yes, %) Cardiomyophathy (yes, %) Valvular disease (yes, %) Others (yes, %) Past medical history Hypertension (yes, %) Diabetes mellitus (yes, %) Dyslipidemia (yes, %) Arterial blood gas pH pCO2 (mmHg) pO2 (mmHg) HCO3 (mmol/L) SaO2 (%) Lactate (mmol/L) Laboratory data Total bilirubin (mg/dl) Uric acid (mg/dl) Sodium (mmol/L) Potassium (mmol/L) Hemoglobin (g/dl) BUN (mmol/L) Creatinine (g/dl) CRP (mg/dl) BNP (pg/ml) Medication (cases) during ICU Furosemide (yes, %) Nitroglycerin (yes, %) Nicorandil (yes, %) Carperitide (yes, %) Dopamine (yes, %) Dobutamine (yes, %) ACE-I/ARB (yes, %) b-Blocker (yes, %) Spironolactone (yes, %) Outcome ICU hospitalization (days) Total hospitalization (days) In-hospital mortality (yes, %)
Total (n = 1050)
Female (n = 354)
Male (n = 696)
p-Value
74 (65–81) 354 (33.7%) 846 (80.6%) 35 (25–49) 160 (130–183) 112 (93–130)
79 (70–85) 97 (27.4%) 281 (79.4%) 41 (30–56) 155 (129–180) 112 (92–130)
72 (64–78) 257 (36.9%) 565 (81.2%) 32 (23–44) 160 (130–186) 112 (93–130)
<0.001 0.002 0.510 <0.001 0.072 0.977
440 (42.0%) 168 (16.0%) 130 (12.4%) 237 (22.6%) 71 (6.8%)
107 (30.2%) 55 (15.5%) 25 (7.1%) 132 (37.3%) 32 (9.0%)
333 (47.8%) 113 (16.2%) 105 (15.1%) 105 (15.1%) 39 (5.6%)
<0.001 0.790 <0.001 <0.001 0.038
760 (72.4%) 459 (43.7%) 473 (45.0%)
262 (74.0%) 151 (42.7%) 152 (42.9%)
498 (71.6%) 308 (44.3%) 321 (46.1%)
0.422 0.645 0.348
7.33 (7.20–7.42) 42.5 (33.7–55.8) 88 (66–133) 22 (19–24) 96 (90–98) 1.7 (1.1–3.4)
7.33 (7.22–7.41) 44.0 (34.7–55.0) 92 (67–145) 22 (20–25) 96 (91–98) 1.7 (1.1–3.5)
7.33 (7.19–7.43) 41.7 (33.3–56.7) 86 (65–130) 22 (19–24) 96 (89–98) 1.8 (1.2–3.4)
0.671 0.233 0.151 0.259 0.210 0.571
0.6 (0.4–0.9) 6.8 (5.3–8.1) 140 (137–142) 4.2 (3.9–4.7) 12.4 (10.6–14.2) 23.8 (17.9–34.6) 1.18 (0.90–1.77) 0.64 (0.20–2.22) 785 (418–1399)
0.6 (0.4–0.8) 6.2 (4.8–7.6) 140 (137–142) 4.2 (3.8–4.7) 11.4 (10.1–12.7) 23.3 (17.3–33.0) 1.00 (0.78–1.41) 0.53 (0.17–1.78) 851 (394–1572)
0.6 (0.4–0.9) 7.0 (5.7–8.3) 140 (137–142) 4.3 (3.9–4.7) 12.9 (11.0–14.9) 24.1 (18.1–36.5) 1.32 (1.00–1.88) 0.68 (0.21–2.49) 736 (425–1340)
0.051 <0.001 0.449 0.096 <0.001 0.122 <0.001 0.060 0.356
986 695 155 555 259 228 405 260 371
(93.9%) (66.2%) (14.8%) (52.9%) (24.7%) (21.7%) (38.6%) (24.7%) (35.3%)
332 (93.8%) 233 (65.8%) 41 (11.6%) 166 (46.9%) 76 (21.5%) 59 (16.7%) 132 (37.3%) 65 (18.4%) 127 (35.9%)
654 462 114 389 183 169 273 195 244
(93.9%) (66.4%) (16.4%) (55.9%) (26.3%) (24.3%) (39.2%) (28.0%) (35.1%)
0.892 0.890 0.043 0.006 0.096 0.004 0.547 0.001 0.838
4 (3–7) 28 (17–46) 107 (10.2%)
4 (3–7) 29 (18–52) 43 (12.1%)
5 (3–7) 27 (17–45) 64 (9.2%)
0.360 0.151 0.160
NYHA, New York Heart Association; LVEF, left ventricular ejection fraction measured by echocardiography; BUN, blood urea nitrogen; CRP, C-reactive protein; BNP, brain natriuretic peptide; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ICU, intensive care unit. The p values between females and males were determined using the Mann–Whitney U-test or the x2 test. All numerical data are expressed as the median (25–75% interquartile range).
The Kaplan–Meier curves for the gender differences are shown in Fig. 1. The female patients had a significantly poorer prognosis, and higher rates of cardiovascular cause death. The multivariate Cox regression model identified female gender as an independent predictor of 730-day cardiovascular mortality [hazard ratio (HR), 1.381; 95% CI, 1.018–1.872] (Table 2). In subgroup analysis by significant factors for female including age, LVEF, type of HF, etiology, hemoglobin, and creatinine, in patients over 79 years, female gender significantly increased the cardiovascular death (HR: 1.715, 95% CI: 1.088–2.074) with a significant interaction (p-value for interaction < 0.001). The patients with non-valvular disease also had increased cardiovascular death (HR: 1.616, 95% CI: 1.131–2.304) with a significant interaction (p-value for interaction = 0.010) (Fig. 2). Thus, the higher risk of female relative to male for 730 days cardiovascular death was consistent with the patients over 79 years and with nonvalvular disease. There was significant interaction between the age
and etiology group, and the risk of female relative to male for 730 days cardiovascular death. Older age and a valvular etiology were significant characteristics in female gender, which means that only age was positively associated with female gender among patients with AHF. We paid attention to age factors that were associated with female gender, and performed further evaluations. The prognosis in age category The gender distribution of the AHF patients is shown in Fig. 3. The overall population included 354 (33.7%) female patients and 696 (66.3%) male patients. Among the patients who were over 79 years of age (n = 345), there were 188 (54.5%) female patients. Meanwhile, in the patients who were under 79 years of age (n = 705), there were only 166 (23.5%) female patients. The Kaplan–Meier survival curves showed that the prognosis, including cardiovascular cause death, was significantly poorer
Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015
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Overall Population
among the female patients who were 79 years of age than it was in the male patients who were 79 years of age (p = 0.019) (Fig. 4A). In contrast, there was no significant difference between the male and female patients who were <79 years of age (p = 0.836) (Fig. 4B). The multivariate Cox regression model identified female gender as an independent predictor of 730-day cardiovascular mortality among the patients who were 79 years of age (HR, 1.943; 95% CI, 1.192–3.167; p = 0.001), but not in patients <79 years of age (Table 3).
Cumulative survival
1 0.8 0.6
p=0.005
0.4 male (n=696)
0.2
Discussion
female (n=354)
Comparisons with previous studies
0 0
200
400
600
512 226
411 182
351 155
800 days
Number at risk male female
327 138
Fig. 1. The Kaplan–Meier survival curves showed that the rate of all-cause death within 730 days after admission was significantly lower in the female patients (n = 356) than in the male patients (n = 701).
Although there have been several large cohort registries of AHF patients [18–20], little is known about the gender differences in Asian AHF patients. The gender differences in Acute Decompensated Heart Failure Syndromes (ATTEND) Registry, which is the largest registry of hospitalized HF patients in Asian countries [19], have not been investigated in detail. Meanwhile, the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) [23]
Table 2 The multivariate analyses of the associations between 730-day cardiovascular death and the clinical findings. All patients
Univariate
Gender (female) Laboratory data Age (per 1 year increase) SBP (per 10 mmHg increase) Heart rate (per 1 bpm increase) Creatinine (per 0.1 mg/dl increase) Total bilirubin (per 1 mg/dl increase) Sodium (per 1.0 mmol/L increase) CRP (per 1 mg/dl increase) Hemoglobin (per 1.0 mg/dl increase) LVEF (per 10% increase)
HR
95% CI
1.496
1.131–1.98
1.034 0.853 0.990 1.010 1.131 0.937 1.007 1.003 0.997
1.020–1.047 0.822–0.885 0.985–0.994 1.003–1.016 1.047–1.222 0.915–0.959 0.998–1.017 0.993–1.013 0.919–1.082
Multivariate p-Value
HR
95% CI
p-Value
0.005
1.381
1.018–1.872
0.038
<0.001 <0.001 <0.001 0.004 0.002 <0.001 0.126 0.591 0.951
1.032 0.986
1.017–1.047 0.982–0.99
<0.001 <0.001
1.011 1.142 0.962
1.004–1.019 1.037–1.258 0.938–0.985
0.003 0.007 0.002
HR, hazard ratio; CI, confidence interval; SBP, systolic blood pressure; CRP, C-reactive protein; LVEF, left ventricular ejection fraction measured by echocardiography.
p
All Patients
1.496 (1.131-1.980)
Age ≥79 years Age <79 years
1.715 (1.088-2.704)
LVEF ≥41 % LVEF <41 %
1.264 (0.815-1.959) 1.602 (1.103-2.326)
p=0.081
De novo Re-admission
1.341 (0.916-1.964) 2.103 (1.391-3.179)
p=0.050
Valvular disease Non-valvular disease
0.824 (0.514-1.321) 1.616 (1.131-2.304)
p=0.010
Hb ≤ 12.4 g/dl Hb >12.4 g/dl
1.172 (0.800-1.719) 1.441 (0.922-2.158)
p=0.717
Creatinine ≤ 1.0 mg/dl Creatinine >1.0 mg/dl
2.535 (1.326-4.845) 1.704 (1.223-2.343)
p=0.423
male worse
1.046 (0.685-1.596)
0
1
2
3
4
5
interaction
p<0.001
Female worse
Fig. 2. Forest plot of hazard ratios by patient subgroups for cardiovascular death. Female gender significantly increased cardiovascular death (HR: 1.715, 95% CI: 1.088–2.074) with a significant interaction (p-value for interaction < 0.001). The patients with non-valvular disease increased cardiovascular death (HR: 1.616, 95% CI: 1.131–2.304) with a significant interaction (p-value for interaction = 0.010).
Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015
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female HF patients showed better survival [25]; however, some recent analyses have suggested that male and female patients show similar outcomes [7,8,11,13,26]. It has been reported that gender differences of HF patients may be affected by race [8]. It is therefore important to evaluate the gender differences in Asian patients, especially in Japanese patients. Furthermore, the previous studies included a relatively high percentage of female AHF patients (42–52%); in contrast, 33.7% of the patients in the present study were female [18,19,27]. Thus, there might be several definitive differences between the cohort of the present study and the cohorts of previous studies that investigated the gender of HF patients. The present study reveals the prognostic impact of gender in Japanese patients who were emergently hospitalized due to AHF, and suggests that female patients showed a worse outcome.
250 Number of Patients
5
200
150
100
50
Age, LVEF, and the prognoses of female and male AHF patients
0 ≤40
40-49
50-59
60-69
70-79
80-89
≥90
age Fig. 3. The distribution of the age of the AHF patients. The blue bar shows the male patients; the red bar shows the female patients. There were 1050 AHF patients in the study. Among the patients who were 79 years of age (n = 345), there were 188 female patients (54.5%) and 157 male patients (45.5%). Among the patients who were <79 years of age (n = 705), there were 166 female patients (23.5%) and 539 male patients (76.5%). AHF, acute heart failure.
and Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-2 [9] suggested that female patients with chronic HF were older, and had a lower prevalence of ischemic heart disease, diabetes, smoking, and myocardial infarction. Moreover, female patients with chronic HF had better survival after adjustment for baseline differences [9]. However, these studies only included patients with chronic HF and excluded patients with AHF [24]. The pathophysiology of AHF is considered different from that of chronic HF. Thus, the implications of gender in each condition in Asian individuals, in particular Japanese individuals, might also be different. All of the subjects in the present study were Japanese. Although some previous reports have focused on patients with acute or advanced decompensated HF [7,8,11,13,25,26], all of the subjects in those studies were non-Japanese. Earlier studies suggest that
(A)
Age
Our present study suggested that female AHF patients are characterized by older age, de novo HF, a preserved LVEF, valvular disease, non-cardiomyopathy, non-ischemic heart disease, and low uric acid, hemoglobin, and creatinine levels. Furthermore, female AHF patients were less likely to use a vasodilator (i.e. niconrandil or carperitide) and were less likely to use inotropes (i.e. dobutamine). Female gender was associated with a poorer prognosis, especially among older patients. Older age was a significant interaction with female gender in the AHF patients of the present study. Thus, a higher percentage of the older AHF patients were female. Although the precise reason for this is unclear, previous studies have suggested some hypotheses. First, an etiological issue could be involved. It has been reported that ischemic heart disease frequently develops in middle-aged men and elderly women, and more frequently develops in men than in women [1–4]. In fact, few of the female patients in the present study had ischemic AHF. Valvular disease, such as aortic stenosis, mitral regurgitation or combined valvular disease generally induces HF in elderly patients. These etiological findings might be one reason why older age was associated with AHF. Second, the younger age group included an increased number of male AHF patients. Thus, the patients tended to die earlier and were thus less likely to reach older age. Furthermore, the average life span of men is shorter than that of women; thus, the proportion
(B)
79 years
1 Cumulative survival
Cumulative events
1
Age < 79 years
0.8 0.6 p=0.019
0.4
male (n=157) 0.2
female (n=188)
0
0.8 0.6 p=0.836
0.4
male (n=539) 0.2
female (n=166)
0 0
Number at risk male female
200 101 109
400 72 77
600 48 61
800 44 54
0
200
400
600
Number at risk male female
412 118
340 102
303 95
800 283 85
Fig. 4. Kaplan–Meier curves in each age category. (A) The Kaplan–Meier survival curves show that the prognosis (including cardiovascular death within 730 days) of the female patients was significantly poorer than that of the male patients. (B) The Kaplan–Meier survival curves show that the prognosis (including cardiovascular death within 730 days) of the male and female patients did not differ to a statistically significant extent.
Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015
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Table 3 The multivariate analyses of the associations between 730-day cardiovascular death and the clinical findings in each category. Age <79 years
Gender (female) Laboratory data Age (per 1 year increase) SBP (per 10 mmHg increase) Heart rate (per 1 bpm increase) Creatinine (per 0.1 mg/dl increase) Total bilirubin (per 1 mg/dl increase) Sodium (per 1.0 mmol/L increase) CRP (per 1 mg/dl increase) Hemoglobin (per 1.0 mg/dl increase) LVEF (per 10% increase)
Univariate HR
95% CI
1.046
0.685–1.596
0.836
1.031 0.822 0.987 1.011 1.150 0.926 1.008 1.004 0.995
1.008–1.054 0.786–0.860 0.981–0.993 1.004–1.019 1.063–1.243 0.902–0.951 0.998–1.018 0.996–1.012 0.891–1.111
Age 79 years
Gender (female) Laboratory data Age (per 1 year increase) SBP (per 10 mmHg increase) Heart rate (per 1 bpm increase) Creatinine (per 0.1 mg/dl increase) Total bilirubin (per 1 mg/dl increase) Sodium (per 1.0 mmol/L increase) CRP (per 1 mg/dl increase) Hemoglobin (per 1.0 mg/dl increase) LVEF (per 10% increase)
Multivariate p-Value
HR
95% CI
p-Value
0.007 0.822 <0.001 0.004 <0.001 <0.001 0.126 0.304 0.928
1.036 0.984
1.012–1.061 0.979–0.988
0.003 <0.001
1.009 1.133 0.959
1.000–1.017 1.020–1.258 0.931–0.988
0.040 0.020 0.006
p-Value
HR
95% CI
1.943
1.192–3.167
0.001
0.992
0.984–0.999
0.030
0.855
0.741–0.987
0.033
Univariate
Multivariate
HR
95% CI
1.715
1.088–2.704
0.020
1.062 0.919 0.996 1.008 1.110 0.961 1.012 0.964 0.994
1.009–1.118 0.860–0.982 0.989–1.003 0.993–1.023 0.717–1.717 0.921–1.002 0.974–1.052 0.878–1.058 0.981–1.006
0.021 0.012 0.226 0.295 0.640 0.062 0.548 0.442 0.330
p-Value
HR, hazard ratio; CI, confidence interval; SBP, systolic blood pressure; CRP, C-reactive protein; LVEF, left ventricular ejection fraction measured by echocardiography.
of female HF patients in the older age group can be expected to increase. There might be a pathophysiological reason for the poorer outcomes of female AHF patients that were observed in the older age group in the present study. The left ventricular geometry indicated by left ventricular end-diastolic pressure and LVEF was also important for HF patients [28]. Women show greater increases in ventricular and arterial stiffness with age, and have a greater adipose mass than men, which also influences the left ventricular geometry to a greater extent than in men [29,30]. It has also been suggested that women develop increased concentric left ventricular remodeling and less ventricular dilation in response to chronic arterial hypertension in comparison to men [31]. Women can therefore be expected to develop HF year by year. Given that the extent of concentric ventricular remodeling is increased in women, and the possibility that this might be associated with a greater loss of diastolic function in the heart of the elderly at the same generation in elderly age, it might be responsible for the worse outcomes in female patients with AHF. We also found that women showed higher LVEF values, and that the outcomes of female patients with a reduced LVEF were poorer in comparison to men with a reduced LVEF. Although the data detail was not shown in the present study, prognostic impact regarding LVEF and gender would be an important issue and should be discussed. Females accounted for a higher proportion of the study population in some previous studies of HF patients with preserved EF values [12,26]. The results of the present study were consistent with this finding. One possible reason could be genderbased differences in the etiologies of AHF. Thus, the LVEF was generally preserved in the patients with valvular disease. Furthermore, some studies have shown that female HF patients with a preserved LVEF may be more sensitive than male patients to cardiac remodeling due to pressure overload [11,32]; another study suggests that reactive oxygen species are more easily produced in women [33]. These molecular findings might explain why AHF developed in different percentages of men and women, even when they showed the same LVEF values.
Previous studies have shown that male and female patients with reduced and preserved EF values have similar rates of inhospital mortality and long-term outcomes [10,12]. Furthermore, Zsilinszka et al. examined sex differences in AHF patients with a preserved LVEF who were admitted to an emergency department and concluded that male and female patients showed similar 30day and 180-day mortalities [26]. In the present study, however, the prognosis of female patients was poorer among the group of patients with a reduced LVEF. Although the reason for this finding is unclear, many clinical trials for HF patients with a reduced LVEF have shown that women are less likely to have coronary artery disease as an underlying risk factor and they are more likely to have hypertension [8]. Male AHF patients with a reduced LVEF might be categorized as having ischemic heart disease, while female patients might be categorized as having non-ischemic heart disease (such as dilated cardiomyopathy, the dilated phase of hypertensive heart disease, and end-stage valvular disease). The poor prognosis of female patients with a reduced LVEF might be explained by these etiological characteristics. Overall, the findings suggest the presence of a reciprocal relationship between age and LVEF. As HF patients become older, the population of HF patients with a preserved LVEF would increase. Due to the widespread primary prevention of ischemic heart disease, which causes a reduced LVEF, the incidence of ischemic heart disease would become lower. In the future, the baseline characteristics of AHF might change and the prevalence of female patients might become similar; thus, in the near future, most AHF patients may have a preserved LVEF. There are currently no therapeutic guidelines regarding genderbased treatments. A previous study of hospitalized chronic HF patients revealed that women were equally likely to receive diuretics, but less likely to receive vasodilators or to be treated with evidence-based therapy than men [11]. Early management with intravenous therapeutic agents is reported to be important, and to be associated with a modestly high risk of in-hospital mortality and a longer length of hospital stay in emergently
Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015
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hospitalized AHF patients (particularly older patients) [34]. A gender analysis of the ADHERE registry showed that women were less likely to receive vasodilators and procedure-oriented therapy [11]. In our analysis, we also found that women with AHF were hesitant to receive vasodilators or inotropes such as nocorandil, carperitide, and dobutamine; this might have led to adverse outcomes in our present female cohort. Aggressive treatment in the early phase of AHF might be needed to improve the prognosis of female AHF patients in the emergency department. Study limitations The present study is associated with several limitations that should be considered when interpreting the results. First, the study was performed at a single center and was not a prospective randomized controlled trial. It is therefore possible that unmeasured variables, which might have affected the results, were present. Second, our study population was limited to patients who were admitted to the ICU; AHF patients who were admitted to general wards were excluded from this study. Nonetheless, the majority of patients with severely decompensated AHF were admitted to a ‘‘closed ICU’’ and treated by cardiologists in our institute. Thus, the majority of patients with severely decompensated AHF were admitted to the ICU. In fact, the characteristics of the patients in the present study were similar to those of another prominent Japanese registry study. Third, 4 patients with missing LVEF data (female, n = 2; male, n = 2) were included in the present study. Finally, we could not include the factors from the compensated phase in the multivariate analysis. The medications used, treatments, and other factors in the compensated phase might be additional variables that can be used for predicting the prognosis in both genders. Conclusion Female gender was an independent predictor of the prognosis of patients who were emergently hospitalized for AHF. The female patients were typically elderly and had a preserved LVEF, de novo HF, and valvular disease. In particular, elderly age was associated with adverse outcomes in female patients with AHF. Funding sources This research received no grants from any funding agency in the public, commercial, or not-for-profit sectors. Conflict of interest The authors declare no conflicts of interest in association with the present study. Acknowledgments We are grateful to the staff of the ICU and the medical records office at Nippon Medical School Chiba Hokusoh Hospital for collecting the medical data. References [1] Lee CY, Hairi NN, Wan Ahmad WA, Ismail O, Liew HB, Zambahari R, Ali RM, Fong AY, Sim KH, NCVD-PCI Investigators. Are there gender differences in coronary artery disease? The Malaysian National Cardiovascular Disease Database – Percutaneous Coronary Intervention (NCVD-PCI) Registry. PLOS ONE 2013;8:e72382. [2] Zhang ZM, Rautaharju PM, Prineas RJ, Rodriguez CJ, Loehr L, Rosamond WD, Kitzman D, Couper D, Soliman EZ. Race and sex differences in the incidence and prognostic significance of silent myocardial infarction in the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2016;133:2141–8.
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Please cite this article in press as: Nozaki A, et al. The prognostic impact of gender in patients with acute heart failure – An evaluation of the age of female patients with severely decompensated acute heart failure. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.11.015