Influence of Sex on Mortality in Hospitalized Patients With Congestive Heart Failure and Preserved or Depressed Systolic Function

INTRODUCTION

Congestive heart failure (CHF) is a major cause of mortality, morbidity, and health expenditure.^1-3 Although several studies have described demographic markers with prognostic value in this condition, only age has shown to be a strong predictor of survival in virtually all of them.^4-7 In contrast, there is some controversy regarding the impact of sex on mortality in patients hospitalized for CHF. In some studies, most of which involve patients with depressed left ventricular systolic function (CHF-DSF), male sex was shown to be an independent predictor of mortality during follow-up,^8-11 whereas in others no differences in survival were found according to this variable.^12,13 In fact, among the patients included in the SOLVD study, mortality in women was significantly higher than in men.¹⁴ Martínez-Sellés et al¹⁵ recently reported that mortality in men with CHF-DSF is significantly higher than in women, with no differences between sexes in the group with CHF and preserved systolic function. Despite these efforts, the current information regarding the influence of sex on the prognosis of patients with CHF is scant and discordant, particularly in the population with preserved left ventricular systolic function (CHF-PSF).

The characteristics of the patients included in the available studies may have played a part in conditioning the results. In some of them only a limited percentage of women are included,^9,10 and this is in line with what is observed in nearly all the clinical trials in CHF. Additionally, many of them offer no information on ventricular function⁸ or limit the study only to patients with CHF-DSF.^9,10 Furthermore, differences in the clinical profile, with a higher percentage of ischemic heart disease in men,¹⁶ in the use of drugs with recognized prognostic benefit,¹⁷ and in the quality of the clinical monitoring and follow-up,¹⁸ as well as a potential difference in the natural history of the disease between men and women could justify the differences in the findings obtained.

Our aim was to study the influence of sex (women vs men) on long-term survival in patients hospitalized for CHF, in both the total population with this condition and in the subgroups with CHF-PSF or CHF-DSF.

PATIENTS AND METHOD

Study population

Data were compiled from the medical records of all patients admitted for CHF and discharged from the Cardiology Department of Hospital Clínico Universitario de Santiago de Compostela, Spain, between 1 January 1991 and 31 December 2002. The present analysis includes all patients who underwent an electrocardiogram with assessment of left-ventricular systolic function (LVSF) during the first days after hospital admission. The patients who were not included in the analysis because echocardiography was not available (407 patients) were older (73.0±11.4 vs. 69.2±11.8 years; P<.001); no other statistically significant differences with respect to those undergoing echocardiography were observed.

A modification of the Framingham criteria was used to define CHF. Major criteria included nocturnal paroxysmal dyspnea, orthopnea, crepitant rales, jugular vein enlargement, third heart sound, and radiological evidence of pulmonary congestion and cardiomegaly; minor criteria were exertional dyspnea, edema, hepatomegaly, and pleural effusion. A diagnosis of CHF was established when at least 2 of the major criteria, or 1 major and 2 minor criteria, were met. When selection of a patient was based on minor criteria, other possible causes for the signs or symptoms were ruled out.

Systolic function was considered to be preserved when the left-ventricular ejection fraction (LVEF) as determined by echocardiography was ≥50% and depressed when LVEF was <50%.

Data were compiled on the main clinical characteristics, additional examinations performed, treatment prescribed at hospital discharge, and duration of the hospital stay. Among patients admitted more than once for CHF during the 12-year study period, only the first admission with echocardiographic data on LVSF was included in the analysis.

Clinical data were recorded prospectively over the entire period of the study. However, information for the survival analysis was obtained from the hospital's general files and a telephone interview performed in April 2003.

Selection of patients for inclusion in the study and data collection were carried out by staff members of the Cardiology Department with extensive experience in CHF.

Etiology

A patient was considered to have ischemic heart disease when one of the following factors was present: diagnosis of ischemic heart disease, prior hospitalization for an acute coronary event (acute myocardial infarction or unstable angina), prior surgical or percutaneous myocardial revascularization, presence of pathological Q-waves on the electrocardiogram (ECG) performed during hospitalization, or coronary angiography showing ≥50% stenosis in at least 1 coronary vessel. The diagnosis of valve disease was established on the basis of clinical criteria and findings from the echocardiographic or cardiac catheterization studies. Most of the patients were not eligible for a surgical procedure because they had advanced heart disease and comorbid conditions. Patients with valvular heart disease amenable to surgical or percutaneous correction were excluded. Hypertension (HT) was established in cases with a prior diagnosis of this condition and in patients requiring antihypertensive drugs for blood pressure control. The diagnosis of idiopathic dilated cardiomyopathy was reserved for patients with depressed systolic function and left ventricular enlargement, and no evidence of the etiologic conditions mentioned above.

Statistical Analysis

Categorical and dichotomous variables were compared with the chi-square or Fisher exact text and expressed as a percentage. Continuous variables were compared with the Student t test for between-group comparisons and expressed as the mean ± standard deviation.

Survival curves were obtained with the Kaplan-Meier method in the total patient population and in the CHF-DSF and CHF-PSF subgroups, for women and for men. The log rank test was used to assess differences in survival between the groups.

A univariate analysis was performed to determine which variables had an influence on prognosis in the overall group of patients studied. Lastly, multivariate analysis of variance was done using the Cox proportional hazards model, which simultaneously included all the significant variables from the univariate analysis as well as those considered necessary to adjust the model (HT, sex, and LVSF). In addition, independent multivariate analyses were performed in the subgroups of patients with CHF-PSF and CHF-DSF hospitalized during the years 1991-1996 and 1997-2002, in which sex was adjusted by variables with potential prognostic influence (age, etiology, diabetes mellitus, HT, hyperlipidemia, left bundle branch block, NYHA functional class, and angiotensin converting enzyme inhibitor [ACEI], or beta-blocker treatment prescribed at hospital discharge).

RESULTS

Characteristics of the Sample

The population sample consisted of 1252 patients hospitalized for CHF during the study period, in whom an echocardiographic study with LVSF determination was performed during the hospital stay. Mean age was 69.4±11.7 years (range, 16-98 years) and median hospital stay was 12.0 days. At the time of admittance, 41.7% of the patients were in NYHA functional class IV. Chest radiography showed cardiomegaly in 79.4% of the cases and alveolar edema in 19.4%. The most prevalent arrhythmia was atrial fibrillation, present in 33.9%. Left ventricular systolic function was depressed in 60.2% of the patients. The main clinical characteristics of the sample are shown in Table 1.

Etiology

The most prevalent cardiovascular risk factor was HT, present in 56% of the patients. The most frequent type of cardiac condition was ischemic heart disease, diagnosed in 48.6% of the cases; 66.8% of these patients also presented concurrent HT. The prevalence of the different risk factors and etiologies analyzed are shown in Table 2.

Treatment

Diuretic treatment, administered in 75.7% of the patients, was the most common drug therapy prescribed at hospital discharge, followed by ACEIs in 62.7% of the cases. Beta-blockers were given in 28% of the patients and digoxin in 30.8%. Pharmacological treatment prescribed at hospital discharge is summarized in Table 3.

Sex

Among the total population studied, 767 patients were men (61.3%) and 485 women (38.7%). Mean age was significantly higher in the group of women (73.4±10.0 vs 66.8±11.9 years; P<.001) (Table 4). Differences in the clinical characteristics between the 2 groups were limited to the presence of a third heart sound, jugular venous enlargement, and hepatomegaly, which were more frequent among men. There were significant between-group differences in the LVSF, with a predominance of depressed LVSF in men (68.1%) and preserved LVSF in women (52.2%). Significant differences in the etiology between the groups included a higher percentage of HT and diabetes mellitus in women, whereas smoking was more frequent among men. No significant differences were found for hyperlipidemia. Ischemic disease was the most frequent type of cardiac pathology in both men and women, although its prevalence was higher in men (54.2% vs 44.1%); valvular disease was more predominant in women (28.9% vs 15.6%) and occupied the second place after ischemic disease. Idiopathic dilated cardiomyopathy was more frequent among men (12.0% vs 5.4%), and no significant differences were found in the percentages of the remaining heart diseases.

With respect to the drug treatment given at the time of discharge, there were significant differences in ACEI and beta- blocker prescription, which were more frequent in men than women (65.6% vs 58.1%; P=.01, and 30.4% vs 24.3%; P=.02, respectively). There were no significant between-group differences relative to the remaining pharmacological groups analyzed. Pharmacological treatment and differences according to sex are shown in Table 5.

Survival

Reliable survival data were available for 1133 patients (90.5%). Median follow-up in these patients was 2.3 years. At completion of follow-up, 668 patients had died (41.0%); one-year, three-year and five-year mortality was 16.0%, 33.3%, and 49.1%, respectively, with a median survival of 5.1±0.4 years (95% confidence interval [CI], 4.3-5.9 years). In the univariate analysis assessing the various clinical variables and cardiovascular risk factors, age (hazard ratio [HR]=1.044; 95% CI, 1.035-1.054; P<.001), presence of crepitant rales on pulmonary auscultation (HR=1.326; 95% CI, 1.048-1.677; P=.019), jugular vein enlargement (HR=1.218; 95% CI, 1.011-1.467; P=.038), radiological alveolar edema (HR=1.779; 95% CI, 1.390-2.277; P=.001), diabetes mellitus (HR=1.597; 95% CI, 1.311-1.945; P<.001), and ischemic or valvular heart disease (as compared to idiopathic dilated cardiomyopathy and other heart diseases; P<.001) were significantly associated with lower survival. Male sex (HR=1.142; 95% CI, 0.950-1.373; P=.158) and the remaining variables showed no significant association with the prognosis. When the influence of treatment prescribed at discharge was assessed in the univariate analysis, diuretics (HR=1.360; 95% CI, 1.058-1.748; P=.017), digoxin (HR=1.267; 95% CI, 1.023-1.569; P=.030) and nitrates (HR=1.422; 95% CI, 1.154-1.741; P=.001) were associated with lower survival, whereas ACEI (HR=0.592; 95% CI, 0.480-0.730; P<.001), beta-blockers (HR=0.662; 95% CI, 0.499-0.879; P=.004) and anticoagulants (HR=0.582; 95% CI, 0.441-0.768; P<.001) were associated with a more favorable prognosis.

In the univariate analysis performed in the CHF-PSF and CHF-DSF subgroups, male sex again showed no significant influence on survival (HR=0.950; 95% CI, 0.711-1.269; P=.727, and HR=0.817; 95% CI, 0.638-1.047; P=.111, respectively).

Similarly, in the Kaplan-Meier analysis performed to determine the influence of sex on the periods 1991-1996 and 1997-2002, no significant differences in survival were found between men and women; median survival was 5.6 years (95% CI, 3.8-7.3) for men and 5.0 years (95% CI, 3.9-6.1) for women (P=.221) in the first period and 4.3 years (95% CI, 3.3-5.3) versus at 5.3 years (95% CI, 4.1-6.4), respectively (P=.439) in the second period.

Overall survival curves for men and women (Figure 1) showed no significant differences. Nor were there differences between sexes in the individual survival analyses of patients with CHF-PSF (Figure 2) or CHF-DSF (Figure 3).

Figure 1. Survival curves (Kaplan-Meier) for men and women in the total sample.

Figure 2. Survival curves (Kaplan-Meier) for men and women in the group with preserved systolic function (ejection fraction ≥50%). EF indicates ejection fraction.

Figure 3. Survival curves (Kaplan-Meier) for men and women in the group with depressed systolic function (ejection fraction <50%).

In the multivariate analysis for the overall group according to Cox's proportional hazards model, which included all the significant clinical variables found in the univariate ana lysis as well as those considered necessary to adjust the model (HT, sex, and LVSF), sex showed no significant influence on the prognosis. Results of the multivariate analysis to determine the variables with an independent influence on the prognosis are summarized in Table 6. There were no statistically significant findings.

DISCUSSION

The results of our study, which included a large number of patients hospitalized for CHF and a lengthy follow-up, indicate that sex did not significantly influence survival, either in the univariate analysis or after adjustment for other variables with prognostic influence (particularly for age). Moreover, the absence of prognostic value for this factor was also observed in the CHF-PSF or CHF-DSF patient subgroups. It is important to highlight that, despite the lack of significant differences in survival between sexes in the overall population of patients, the HR for mortality in men vs. women was 1.3 with a 95% CI at the lower end of virtually 1 (0.98-1.60), a fact indicative of the trend toward lower survival among men.

Nevertheless, the similarity of the survival curves for men and women in the first years, when the number of patients lost to follow up was lower, is quite striking, particularly in the overall analysis, a fact that reinforces the lack of association between patient sex and prognosis in our study.

The series studied included only hospitalized patients. This might limit the applicability of our findings to the overall CHF population, and we cannot rule out that other variables which were not included in the analysis might have had an effect on the results. It should be kept in mind that our series was comprised exclusively of patients admitted to the Cardiology Department of our Hospital, accounting for about 40% of all the hospitalizations for this disease (60% of the patients are admitted to the Internal Medicine Service, and information was not available for them). In addition, changes in the therapeutic approach used during follow-up might have had an influence on the patients' prognosis. Lastly, the loss to follow-up of 9.5% of the patients in the total group is another of the limitations of our study, particularly because the main finding (HR for mortality in men vs women of 1.3 [95% CI, 0.98-1.60]) has a value at the limit of statistical significance.

The characteristics of the patients included in our series are similar to those described in other studies,^4,6,11,15 with a higher percentage of men hospitalized for CHF. The women were older and had a higher prevalence of HT and diabetes mellitus than men. Moreover, in women there were more cases of CHF-PSF, which among other reasons, could be due to the fact that the proportion of patients with ischemic cardiomyopathy (in particular, a history of myocardial infarction) was significantly higher in men. These facts could suggest that the absence of differences in the prognosis between men and women included in our series might be because the women were older and presented CHF-PSF in a higher proportion. Even though age is the main determining factor of mortality in all the studies, one could speculate that a possibly better prognosis in patients with CHF and preserved systolic function would balance the mortality. Nevertheless, we found no significant differences in mortality between the patient groups with CHF-PSF or CHF-DSF and, after adjusting for age, sex still was not a determinant of differences in the prognosis.

Several factors justify the higher percentage of women among the group of patients with CHF-PSF. The larger number of cases of ischemic heart disease in men and HT in women could have exerted a certain influence. It has been described both in animals and humans that women develop a greater degree of concentric hypertrophy in situations of pressure overload as compared to men.^19,20 Furthermore, in men in this situation, the left ventricle is more prone to dilation and progressive deterioration of systolic function.²¹ These facts, together with the higher prevalence of ischemic heart disease in men,¹⁶ could explain the differences in the pathophysiologic pattern of CHF in relation to sex (CHF-PSF vs CHF-DSF), at least in patients with CHF secondary to HT.

There is some controversy as to the influence of sex on the prognosis of patients with CHF. Several studies have described a poorer prognosis in men,^8-11 both in the univariate analysis and following adjustment for factors with a potential influence, such as age. Gustafsson et al¹¹ reported that male sex was an independent predictor of mortality in a large series of hospitalized CHF patients. Although sex did not determine differences in the univariate analysis, after adjusting for other variables, particularly age, male sex was a strong determinant of mortality. The elevated prevalence of clinical ischemic heart disease (57% of women and 65% of men) and the surprisingly small number of HT cases (26% of women and 21% of men) could determine the differences with respect to our findings. In our setting, the study by Martínez-Sellés et al¹⁵ in a series of 1065 patients hospitalized with CHF yielded similar results for survival between women and men whose LVEF was >30%. Worse prognosis for men in that study was limited to the group with severely depressed LVSF, suggesting that systolic dysfunction is a long-term predictor of mortality in men but not in women with CHF. Several mechanisms might account for the impact of sex on the relationship between LVEF and the prognosis of patients with CHF. Women may possess protective mechanisms against CHF due to systolic dysfunction; differences have been observed between men and women in ventricular remodeling, myocardial ion channel activity, skeletal muscle adaptation, ventricular arrhythmias and neurohormonal activity, as well as the higher incidence of myocyte apoptosis in women with CHF.²² The differences in survival between men and women in our series did not reach statistical significance in either the CHF-PSF or CHF-DSF group. However, the LVEF value (>50% or <50%) used to classify the patients might have had an effect on the results in the group of patients with systolic dysfunction.

In contrast to reports showing an influence of sex on mortality in CHF patients^8-11 and in line with our data, several studies have observed no significant impact of sex on the prognosis of patients with CHF.^7,12,13 In some of them significance in the univariate analysis was lost after adjusting for other variables. Notably, in the SOLVD series, mortality was higher in women than men.¹⁴ It has been speculated that exclusion of patients with CHF-PSF might have played a part in determining these results; nevertheless, this justification is not consistent with the findings of Martínez-Sellés et al.¹⁵ It has also been suggested that the scant number of women included (in some studies <20% of the sample) might be an obstacle to obtaining significant differences; however, our data do not seem to confirm this hypothesis since the size of our group of women was similar to that of men.

We believe that efforts should be intensified to achieve more effective prevention of CHF through better control of hypertension and ischemic heart disease, and that each individual patient should receive the therapeutic strategy that has been shown to prolong and improve the quality of life in this population. In this respect, less extensive use of ACEI has been described in women with CHF, even though there is no evidence of differences in the efficacy of this treatment according to sex.

Received May 6, 2004.
Accepted for publication June 22, 2005.

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Correspondence: Dr. J.R. González-Juanatey.
Servicio de Cardiología. Hospital Clínico Universitario.
Choupana, s/n. 15706 Santiago de Compostela. A Coruña. España.
E-mail: [e-mail]