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European Journal of Heart Failure 2004 6(6):781-786; doi:10.1016/j.ejheart.2003.12.023
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© 2004 European Society of Cardiology

Sex-related bedside clinical variables associated with survival of older inpatients with heart failure

Natan Cohen*, Eduard Ilgiyaev, Dorit Almoznino-Sarafian, Irena Alon, Miriam Shteinshnaider, Shulamit Chachashvily, David Modai and Oleg Gorelik

Department of Internal Medicine ‘F’, Assaf Harofeh Medical Center, Zerifin, Affiliated to Sackler Faculty of Medicine Tel-Aviv University, 70300, Israel

* Corresponding author. Tel.: +972-08-9779991/4; fax: +972-08-9779796. E-mail address: internal6{at}asaf.health.gov.il


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Little is known about sex-related differences in factors affecting prognosis of heart failure (HF). We prospectively investigated the relationship between bedside clinical variables and survival of older females vs. males with HF.

Methods: Included were consecutive unselected inpatients, age ≥60 years, admitted for various acute conditions. HF was chronic and of diverse etiologies. Follow-up extended up to 5 years. All-cause mortality was registered and statistically analyzed for association with in-hospital clinical variables.

Results: Included were 162 females and 200 males. Survival rates were 52.4% and 59%, respectively, (P=0.1). Advanced age and renal dysfunction (RD) were associated with low survival in both sexes (P<0.03 and 0.02, P<0.001 and 0.01, respectively). An association with low survival was found with respect to; admission for pulmonary edema (P<0.02), using furosemide ≥80 mg/day (P<0.005) and severe HF [NYHA class III–IV (P<0.01)] in females, as well as for hypokalemia (P<0.03) and hypocalcemia (P<0.03) in males. On multivariate analysis RD (P<0.001), increasing age (P=0.008) and furosemide dosage ≥80 mg (P=0.02) were most significantly associated with low survival in females, while RD only was significantly associated with low survival in males (P=0.03).

Conclusions: Several clinical variables, which affect prognosis in older HF patients are sex-related and probably carry practical significance.

Key Words: Heart failure • Sex • Prognosis • Mortality • Older age

Received September 4, 2003; Revised December 1, 2003; Accepted December 24, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Various reports have demonstrated sex-related differences in the course, morbidity and mortality from cardiovascular diseases [1–3]. Coronary heart disease, myocardial infarction and valvular diseases are common underlying conditions of heart failure (HF) in women [4,5]. However, women with HF are older than men [4,5], are more likely to suffer from hypertension [5,6], diabetes mellitus [4,7] and symptoms of HF, despite similar left ventricular ejection fractions (LVEF) [8]. Moreover, prevalence of HF secondary to diastolic dysfunction associated with diabetes mellitus or hypertension is higher in women than in men [3–6,8,9].

HF is becoming an ever-growing burden both epidemiologically and economically, especially in older age [5,10]. There is ample information concerning various factors affecting survival in HF [3,7,10–16]. In view of the sex-related pathophysiologic differences, it is conceivable that similar factors carry different sex-based prognostic consequences. Information regarding the impact of clinical variables on survival of older females compared to males with HF is scarce [5,12,17,18]. Such information may potentially produce practical approaches capable of improving the course and outcome. The present investigation was therefore undertaken to scrutinize the effects of various simple bedside clinical variables on survival of older females vs. males with chronic symptomatic HF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Subjects
Consecutive unselected furosemide-treated HF patients, aged ≥60 years, admitted for pulmonary edema or other acute conditions, were included. HF was chronic, grade II–IV New York Heart Association (NYHA), and of various etiologies. The diagnosis of chronic HF was based on data from previous hospitalizations and/or outpatient records. These included typical symptoms (shortness of breath, orthopnea, paroxysmal nocturnal dyspnea), physical signs (edema, pulmonary rales, gallop rhythm, displaced left ventricular apical impulse) and radiographic evidence of pulmonary congestion (pulmonary venous redistribution, basal or perihilar vascular blurring, Kerley B lines, pulmonary edema and pleural effusions). Patients who died during hospitalization or with advanced malignancy were excluded. The investigation conforms with the principles outlined in the Declaration of Helsinki and was approved by the local ethics committee. All subjects gave written informed consent to participate in the study.

2.2. Study design
On admission, bedside clinical, electrocardiographic, echocardiographic and laboratory variables, as well as drug use, were recorded. Following discharge patients were contacted annually. At the end of the follow-up period these variables were subjected to statistical analysis in respect to eventual association with survival within the female and male subgroups separately. Management of patients was conducted exclusively by primary care physicians. All-cause mortality was the end point of this study. Death was confirmed by hospital or outpatient death certificates.

2.3. Definition of data collected
Anemia, hyponatremia, hypokalemia, hypocalcemia and renal dysfunction (RD) were defined as hemoglobin <12 g/dl, serum sodium <133 mmol/l, potassium ≤3.5 mmol/l, calcium ≤2.0 mmol/l and creatinine >132 µmol/l, respectively. Diagnosis of pulmonary edema was confirmed by presence of severe shortness of breath, lung rales, pulmonary vascular enlargement and/or frank edema on chest X-ray. Cardiac arrhythmias were defined as atrial or ventricular premature beats >6/min, couplets, atrial fibrillation, supraventricular or ventricular tachycardia. Cardiac conduction disturbances included atrioventricular or bundle-branch block. Data on LVEF, where available, were obtained from the following examinations performed within the previous 6 months in our or other institutions: two-dimensional color echocardiography, radionuclide imaging or cardiac catheterization. Systolic HF and isolated diastolic HF were defined as decreased LVEF (<50%) or preserved LVEF (≥50%), respectively, in the presence of chronic HF.

2.4. Statistical analysis
To analyze the prognostic significance of different variables, survival curves were plotted using the Kaplan–Meier method. Mantel-Cox and Breslow's tests were applied to evaluate statistical significance of differences between the curves. A P-value of ≤0.05 was considered significant. Variables with a P-value of ≤0.1 were further subjected to the Cox proportional hazards model to identify the variables, which most significantly affected mortality.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Baseline characteristics
Included were 362 patients, of whom 162 (44.8%) females and 200 (55.2%) males. Mean age (±S.D.) was 75.8±8.1 in women and 74.7±7.2 in men (P=0.2). The respective causes of admission in the female vs. male subgroups were: pulmonary edema (37.3% vs. 40%), acute coronary syndrome (24.7% vs. 28%), infectious diseases (22.8% vs. 17%), cardiac arrhythmias (8% vs. 11%), exacerbation of chronic obstructive pulmonary disease (6.8% vs. 10%), cerebrovascular accident (4.9% vs. 3%) and other conditions (11.1% vs. 8%). Some patients were admitted for combined and interrelated disorders.

The prevalence of renal dysfunction was higher in males (56.8% vs. 28.3%), while diastolic HF and anemia were more frequent in females [38.6% (34 of 88 patients) vs. 12.7% (15 of 118 patients) and 48.4% vs. 37.9%, respectively). Therapy included ACE inhibitors or angiotensin II receptor blockers in 56.8% of females vs. 49.5% in males, calcium channel blockers 34.6% vs. 34.5%, digoxin 26.5% vs. 28.5% and β-blockers 12.3% vs. 12.5%, respectively. Only 4 women were on hormonal replacement therapy.

3.2. Survival in the entire HF group
The follow-up period extended up to 5 years. Survival rate was 52.4% in females and 59% in males, the respective mean survival duration was 30.7 and 37.2 months (P=0.1).

3.3. Survival in the female subgroup
Table 1 depicts variables significantly associated with low survival in the female subgroup. It can be seen that advanced age, admission for pulmonary edema, NYHA class III–IV, RD and a furosemide dose ≥80 mg/day, were associated with low survival (P<0.03, 0.02, 0.01, 0.001 and 0.005, respectively). Digoxin treatment (P<0.06), diabetes mellitus (P=0.1) and presence of anemia (P=0.09) tended to be associated with low survival in this subgroup. Fig. 1 illustrates the Kaplan–Meier estimates of survival in females with respect to variables associated with low survival.


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  		Table 1 Effect of different clinical variables on survival in females with heart failure

 


Figure 1
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  		Fig. 1 Kaplan–Meier curves showing significant low survival in females with admission for pulmonary edema (a), renal dysfunction (b), NYHA grade III–IV (c) and furosemide dosage ≥80 mg/day (d).

 
3.4. Survival in the male subgroup
Table 2 demonstrates that in the male subgroup, advanced age, hypokalemia, hypocalcemia and RD were associated with low survival (P<0.02, 0.03, 0.03 and 0.01, respectively). Fig. 2 illustrates survival curves according to Kaplan–Meier method regarding the presence of RD and hypokalemia.


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  		Table 2 Effect of different clinical variables on survival in males with heart failure

 


Figure 2
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  		Fig. 2 Kaplan–Meier estimates of survival in the male subgroup in respect to the presence of renal dysfunction (a) and hypokalemia (b).

 
Hypertension, coronary heart disease, chronic obstructive pulmonary disease, cardiac conduction disturbances, arrhythmias, decreased LVEF, hyperlipidemia and hyponatremia were not associated with increased mortality in either subgroup. Moreover, survival was not affected by treatment with angiotensin II receptor blockers or ACE inhibitors, calcium channel blockers and β-blockers.

3.5. Variables most significantly associated with low survival (on multivariate analysis)
Table 3 demonstrates that RD (P<0.001), increasing age (P=0.008), daily furosemide dosage ≥80 mg (P=0.02) and diabetes mellitus (P=0.06) were most significantly associated with low survival in females. In the male subgroup RD only was significantly associated with low survival (P=0.03).


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  		Table 3 Variables most significantly associated with low survival (multivariate analysis)

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Mortality rate of females with HF is reported to be lower compared to males [3–6,8,12,13,17]. Sex-related differences have been found with respect to myocardial cell function [19–21], ion-channel activity [21,22], cardiac cell growth [20,23], effects of sex hormones [19–21] and pharmacokinetics of various relevant drugs, including furosemide [24,25]. Myocardial response to chronic pressure overload, including hypertension, generates mainly cardiac hypertrophy in women, while men tend to respond by cardiac dilatation [9,23,26]. The predicted functional behavior would consist mainly of diastolic dysfunction as opposed to systolic dysfunction in males [9].

On the basis of these data taken together, one would tend to anticipate that risk variables associated with HF are different in the two sexes. The present study was undertaken to investigate the prognostic significance of relevant simple bedside clinical variables in elderly HF females compared to males. We selected variables known to carry prognostic significance in the context of HF. These variables adjusted for elderly patients were chosen on the basis of easy availability and non-invasiveness. The study was performed in a defined clinical setting. Patients were admitted for a variety of morbid conditions, HF was of any etiology, and following discharge the patients were returned to the exclusive care of their primary physicians. In view of the advanced age, the high prevalence of diverse comorbidities and the recognized difficulty to assign the mechanism of death to HF [27], all-cause mortality was chosen as the end point. These circumstances, therefore, reflect a real life situation.

The present results confirm previously reported data indicating a greater prevalence of anemia [16] and diastolic dysfunction [4–6] in females with HF, while RD prevailed in males [11]. As far as prognostic variables, severity of HF (NYHA grade III–IV), admission for pulmonary edema and maintenance furosemide dosage ≥80 mg/d, were found to be significantly associated with low survival on univariate analysis in female patients. In males, however, hypokalemia and hypocalcemia were significantly associated with lower survival. Further, RD and advancing age affected survival in both sexes. These data were further subjected to multivariate analysis. The independent ominous impact of RD found in both sexes confirms previously reported data [10,11]. Advancing age, high furosemide maintenance dosage and diabetes mellitus were most significantly associated with low survival in females only.

As previously discussed, myocardial metabolic variables, modes of response to stress, notably diastolic dysfunction, are sex-related [8,9]. Some of these factors may negatively affect short- and long-term prognosis of females with HF. This may be the background of the more ominous prognostic significance of severe HF and admission for pulmonary edema in our female vs. male patients.

It has been shown that high maintenance furosemide dose per se, carries a poor prognostic significance in HF [14,28]. Our results indicate that this is mainly borne out in females. In this respect, it is interesting to note that renal furosemide clearance as well as peak natriuretic response were found to be decreased in females compared to males, thus necessitating higher furosemide dosages in female patients [24,25]. This may eventually produce a more severe chronic depletion of effective blood volume in females, which would in turn activate the relevant neurohormonal system. One of the main pathophysiological consequences would be accelerated heart rate contributing to further deterioration of cardiac function.

Recently, it has been shown that digoxin treatment in HF is associated with greater all-cause mortality in females as compared to males [18]. The present results support these data. Hypothetical underlying mechanisms put forward include the deleterious cardiac effect of interaction between digoxin and hormone replacement therapy, as well as progestin induced reduction of renal digoxin clearance with resultant digoxin toxicity [18]. However, our female patients were significantly older than those in that report and only four were on hormonal replacement therapy. We propose that hypomagnesemia, which was found to be more prevalent in HF furosemide-treated females [15], might have also played a role.

Hypokalemia and hypocalcemia were associated with decreased survival in our male patients. Hypokalemia may enhance propensity to severe arrhythmias and compromise cardiac output, which might be potentially fatal. The effect of hypocalcemia on mortality may have been predominantly arrhythmogenic. However, in view of the small number of patients, additional data are required to confirm this finding.

In conclusion, while RD has repeatedly been proven to carry a universal ominous prognostic significance in HF, other variables seem to exert specific sex-related deleterious prognostic effects. Further studies are required to define such variables, their prognostic and eventual therapeutic significance.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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