European Heart Journal (2004) 25, 129135

Clinical research

Female sex is associated with a better long-term

survival in patients hospitalized with congestive
heart failure

Department of Cardiology Y, Bispebjerg University Hospital, Copenhagen, Denmark

Department of Cardiology P, Gentofte University Hospital, Denmark
c
Department of Cardiology, Herlev University Hospital, Denmark
d
Department of Cardiology E, Frederiksberg University Hospital, Denmark
e
Department of Cardiology B, Rigshospitalet, Denmark
b

Received 6 March 2003; received in revised form 24 August 2003; accepted 2 October 2003

KEYWORDS
Gender;
Ischaemic heart disease;
Angiotensin converting
enzyme inhibitors;
Systolic function

Aims Results of previous studies on the influence of gender on prognosis in heart

failure have been conflicting and most studies have been conducted in selected
populations. The aim of this study was determine whether mortality risk in women and
men hospitalized with congestive heart failure is different.
Methods and results Survival analysis of 5491 consecutive patients admitted with
congestive heart failure to 34 Danish hospitals between 19931996. Follow-up time
was 58 years. Forty percent of the patients were female. Females were older, had
less evidence of ischaemic heart disease and their left ventricular systolic function
was preserved to a greater extent than in males. Men were more often treated with
ACE inhibitors. During the follow-up period 1569 women (72%) and 2386 (72%) of the
men died. When the age difference between men and women was adjusted for, male
gender was associated with an increased risk of death (RR 1.25 (1.171.34)) and the
increased risk was confirmed in a multivariate model containing several covariates.
Conclusion In patients hospitalized with congestive heart failure male gender
is an independent predictor of mortality. Female heart failure patients may be
under-treated with ACE inhibitors.
2003 Published by Elsevier Ltd on behalf of The European Society of Cardiology.

Introduction
Congestive heart failure (CHF) is a major and growing
cause of morbidity and mortality.1,2 Although several
studies on prognostic markers in heart failure patients
have been conducted in the past years, it remains
unclear whether females and males have similar out* Correspondence to: Finn Gustafsson, MD, PHD, Department of
Cardiology Y, Bispebjerg University Hospital, Bispebjerg Bakke 23,
DK-2400 Copenhagen NV, Denmark. Tel: +45 35313531; Fax: +45
35313226
E-mail address: [email protected] (F. Gustafsson).

come following admission to hospital with CHF. Some

studies have reported male sex to be an independent
predictor of long term mortality,37 others have shown
no difference in mortality rates2,812 and one large
study has even shown a better outcome in men.13 One
possible explanation for the considerable variation in
the results of these studies may be the selection of the
study populations. Furthermore, several of the studies
are limited by a low number of female patients or by
lack of information on left ventricular (LV) systolic
function. Few studies have been conducted in consecutive cohorts of patients admitted to hospital with CHF.

0195-668X/04/$ - see front matter 2003 Published by Elsevier Ltd on behalf of The European Society of Cardiology.
doi:10.1016/j.ehj.2003.10.003

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on October 27, 2015

Finn Gustafsson a*, Christian Torp-Pedersen a, Hans Burchardt b,

Pernille Buch b, Marie Seibaek b, Erik Kjller c, Ida Gustafsson d, Lars Kber e,
for the DIAMOND Study group

130

The aim of the present study was to evaluate the effect

of gender on the long-term survival in patients hospitalized with CHF, and to assess potential interaction with
common clinical covariates.

Methods
Patients

Statistics
Baseline characteristics for men and women were compared
using continuity adjusted Chi-square tests for discrete variables

and Wilcoxon rank sum tests for continuous variables. Differences in time to death between men and women were analysed
by a two-sided log-rank test. Life table plots were constructed
using the KaplanMeier method. Relative risk (hazard ratio)
(RR), confidence limits and the associated P-value were calculated from maximum likelihood estimates of proportional hazard
models. Multivariate analysis was performed using a backward
selection procedure. The model contained the baseline variables
seen in Table 1 except baseline drug treatment. We anticipated
that the treatment pattern with for instance ACE inhibitors and
diuretics for men and women would differ for reasons not
explained by differences in the prevalence of indication for
treatment between the sexes. Adding such information into the
model would not contribute to the determination of sex as a risk
factor, but would be more likely to bias this particular analysis.
Therefore baseline drug treatment was not included in the
model. The presented RR values are based on the final Cox
regression model containing only the variables, which had not
been excluded by the backward selection procedure. Linearity
of continuous variables was tested by plotting parameter estimates of quintiles versus means of each quintile-and by demonstrating that parameter estimates of quintiles did not differ
significantly from zero in a model containing the continuous
variable. The proportional hazard assumption was tested by
visual inspection of log(-log(survival)) curves. All calculations
were performed on Statistical Analysis System software (SAS
Institute, Cary, NC). A P value <0.05 was considered significant.

Results
Of the 5491 patients included in the present study 2189
(40%) were female. Baseline characteristics according to
sex are presented in Table 1. Females were older and had
less evidence of ischaemic heart disease. In the population as a whole an acute coronary syndrome within the
last 8 weeks was reported only in 3%. Females more often
had a history of arterial hypertension, valve disease and
impaired renal function. Smoking and chronic obstructive
pulmonary disease were more frequent in males. Men and
women were equally distributed with regard to NYHA
functional class but LV systolic function, evaluated by
WMI or EPSS, and LV cavity dimensions were preserved to
a greater extent in the female population. WMI was
obtainable in 95% of the patients with the missing values
(n=251) distributed equally among men and women.
Other missing data were (n): Creatinine: 362, previous
MI: 1, NYHA class: 41, LVEDD: 584, duration of CHF: 437,
EPSS 1075.
More men than women were being treated with ACE
inhibitors at discharge, partly reflecting the higher proportion of males with systolic dysfunction (Table 1).
However, even among patients with LV systolic dysfunction (WMI #1.2) more males (79%) than females (70%)
were treated with ACE inhibitor at discharge (P<0.001,
Table 2). The difference in treatment with ACE inhibitors
between women and men was found in all age groups but
ranged from an absolute 7% lower use in patients above
80 years to only 1% lower use in patients below 60 years.
Few patients (13%) were treated with beta-blockers, and
treatment rates were similar for men and women,
irrespective of LV systolic function.
Baseline characteristics according to sex for the
subgroup of patients with systolic heart failure (WMI

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The DIAMOND-CHF registry comprises consecutive heart failure

patients admitted to 34 Danish Hospitals between November
1993 and July 1996.14 University hospitals as well as medium and
small sized county hospitals participated in the study. Patients
were included in the DIAMOND-CHF registry if a clinical diagnosis
of heart failure was made and if the patient had experienced at
least one episode within the preceding month of shortness of
breath, either on minimal exertion or at rest (New York Heart
Association (NYHA) functional class III or IV), or paroxysmal
nocturnal dyspnoea. In Denmark, this covers practically all heart
failure related admissions since patients with less severe heart
failure symptoms are not likely to be admitted but will be
managed in an out-patient facility. The local investigators made
the decision on whether the underlying cause of the symptoms
was cardiac or not. Patients with acute myocardial infarction
within the last 7 days were not included in the DIAMOND-CHF
screening registry. Twenty-seven percent of the patients in the
registry were subsequently randomized in the DIAMOND-CHF
study, which was a multicentre, randomized, double blind,
placebo controlled trial of the efficacy of the class III
antiarrhythmic agent dofetilide on mortality in patients with
CHF. The study showed no significant effect of dofetilide when
compared with placebo.15
All patients in the registry were screened by obtaining a
clinical history, a physical examination and an ECG. An echocardiogram was recorded on videotape and evaluated in a
central laboratory. Left ventricular systolic function was
assessed by calculation of wall motion index (WMI) as described
previously,16 using a 16-segment model of the left ventricle.17 A
WMI of 1.2 is approximately equivalent to an ejection fraction of
35%. Furthermore, LV systolic function and geometry were
characterized by measurements of mitral E-point ventricular
septum separation (EPSS) and LV end-diastolic diameter (LVEDD)
obtained from 2-D recordings (parasternal longitudinal
axis view). Creatinine clearance was estimated using serum
creatinine values.18
Survival status was obtained from the Danish Central
Personal Registry. In Denmark all residents are given a central
person registry number and all deaths in the country are
registered within 2 weeks from the time of death. Follow-up
time ranged from 5 to 8 years. Including the patients who died
the median follow-up time was 1307 days (interquartile range:
2136 days). For the surviving patients the median follow-up was
2722 days (interquartile range 314 days). During the study 5548
patients were registered. Survival status was not available in
57 patients who were lost to follow-up either due to immigration
or because their central personal registry number was not
recorded. Thus, the study population comprised 5491 patients.
The study was conducted in accordance with the Declaration
of Helsinki II and approved by the Central Danish Ethics
Committee.

F. Gustafsson et al.

Sex and prognosis in heart failure

Table 1

131

Baseline characteristics for 5491 patients admitted with congestive heart failure
Females (n=2189)a

Age (years)
Duration of CHF (months)

75 (6981)
6 (0.236)

History of:
IHD
Angina pectoris
MI
Hypertension
Valve disease
Smoking
COPD
Diabetes
Atrial fibrillation
VT/VF

1160
854
630
592
101
570
440
370
492
25

During hospitalization:
NYHA IIIIV

1358 (63%)

72 (6477)
7 (0.236)

(53%)
(39%)
(29%)
(27)
(5%)
(27%)
(20%)
(17%)
(23%)
(1%)

1959
1332
1395
741
107
1247
786
530
845
73

2086 (63%)

1.6 (1.02.0)
8%
22%
21%
49%
7 (015)
44 (3950)

Drug treatment
ACEI
Digoxin
Beta-blockers
Diuretics

924
1120
299
1838

Creatinine clearance
<20 ml/min
2060 ml/min
>60 ml/min

93 (5%)
1432 (71%)
489 (24%)

(59%)
(40%)
(42%)
(22%)
(3%)
(39%)
(24%)
(16%)
(26%)
(2%)

1.2 (0.81.9)
17%
31%
20%
33%
12 (420)
50 (4358)

(42%)
(51%)
(14%)
(84%)

1868
1759
411
2837

P
<0.0001
0.4
<0.0001
0.3
<0.0001
0.0001
0.01
<0.0001
0.001
0.5
0.009
0.005
0.4
<0.0001

<0.0001
<0.0001

(57%)
(53%)
(12%)
(86%)

<0.0001
0.1
0.2
0.04

42 (1%)
1647 (53%)
1426 (46%)

<0.0001

IHD: ischaemic heart disease; MI: myocardial infarction; EPSS: E-point ventricular septum separation; LVEDD: left ventricular end diastolic diameter;
COPD: Chronic obstructive pulmonary disease; VT/VF: ventricular tachycardia or fibrillation; WMI: Wall motion index; ACEI: angiotensin converting
enzyme inhibitors.
a

Number of patients (%) or median (interquartile range).

#1.2) are presented in Table 2. The differences between

men and women in this group were very similar to those
seen in the overall population.
During the follow-up period 1569 women (72%) and
2386 (72%) of the men died (log rank, P=0.23, Fig.
1). However, when the age difference between men and
women was adjusted for, male gender was associated
with an increased risk of death (RR 1.25 (1.171.34),
P=0.001). A similar risk ratio for men (RR 1.26 (1.17
1.36)) was found in the multivariate analysis, which
included the variables listed in Table 1 except for drug
treatment. In this model also increasing age (RR 1.04
(1.031.04), per year increase), decreasing LV systolic
function (RR 0.60 (0.560.64), per unit increase), diabetes (RR 1.42 (1.301.56), the presence of significant
valve disease (RR 1.40 (1.181.65), duration of heart
failure (RR 1.002 (1.0011.003) per month), chronic
obstructive pulmonary disease (RR 1.36 (1.251.47)) and
creatinine clearance (RR 0.73 (0.690.77) per 20 ml/min
increase) emerged to have independent, negative influ-

ence on survival after admission to hospital with CHF.

The remaining variables in the multivariate model did
not meet the significance criteria, and were therefore
found not to have any independent predictive value.
Performing the analysis using fixed determinants instead
of the backward selection procedure did not significantly
alter the results.
Finally, we conducted formal tests of interaction
between sex and the remaining covariates from the
multivariate model mentioned above. Interaction
between sex and history of ischaemic heart disease was
marginally statistically significant (P=0.03), but for no
variable was an interaction of clinical relevance found.

Discussion
To our knowledge the present study is the first large
investigation of the effect of gender on long-term
survival to include data on LV function in consecutive
heart failure patients admitted to hospital. Results of

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Left ventricular systolic function

Mean WMI
WMI <0.8
WMI 0.81.2
WMI 1.211.6
WMI >1.6
EPSS (mm)
LVEDD (mm)

Males (n=3302)a

132

F. Gustafsson et al.

Table 2

Baseline characteristics for 2147 women and men with WMI #1.2 admitted with congestive heart failure
Females (n=639)a

Age (years)
Duration of CHF (months)

74 (6880)
12 (0.236)
364
248
249
168
31
175
107
127
114

During hospitalization:
NYHA IIIIV

384 (61%)

Drug treatment
ACEI
Digoxin
Beta-blockers
Diuretics

449
398
66
589

Creatinine clearance
<20 ml/min
2060 ml/min
>60 ml/min

33 (5%)
551 (75%)
118 (20%)

(57%)
(39%)
(39%)
(26%)
(5%)
(28%)
(17%)
(20%)
(18%)

(70%)
(62%)
(10%)
(92%)

70 (6377)
12 (0.548)
982
637
760
317
59
566
325
279
376

(65%)
(42%)
(50%)
(21%)
(4%)
(38%)
(22%)
(19%)
(25%)

952 (63%)
1196
974
140
1398

P
<0.0001
0.05
0.0004
0.15
<0.0001
0.009
0.04
<0.0001
0.01
0.5
0.0004
0.2

(79%)
(65%)
(9%)
(93%)

<0.0001
0.3
0.5
0.7

21 (1%)
832 (57%)
604 (41%)

<0.0001

IHD: ischaemic heart disease; MI: myocardial infarction; EPSS: E-point ventricular septum separation; LVEDD: left ventricular end diastolic diameter;
COPD: Chronic obstructive pulmonary disease or asthma; WMI: Wall motion index; ACEI: angiotensin converting enzyme inhibitors.
a

Number of patients (%) or median (interquartile range).

univariate analysis did not suggest any difference in

mortality between men and women. However, when the
analysis was corrected for various covariates (particularly age) male gender emerged as a potent predictor of
death.
In the present study the patients were elderly with a
mean age above 70 years which is a general finding in
unselected heart failure populations irrespectively of
whether they are community or hospital based. The
finding that the men included in this registry were
younger than the women is consistent with previous data
from the Framingham study3 as well as investigations of
hospitalized subjects with CHF.6,8 More men than women
were admitted with heart failure in accordance with
most epidemiological heart failure studies19,20 although a
predominance of female patients has been reported in
some series.21,22
Ischaemic heart disease appeared to be the most
common cause of heart failure in the present population
which is in accordance with most earlier large-scale
analyses,2,23 except the Framingham study in which
hypertension was the most important single cause.24 As
expected, evidence of ischaemic heart disease was more
prevalent in the male population.4,5,2326 In the current
analysis we found that even though the functional status
(NYHA class) among men and women was comparable,
the left ventricle was more dilated and the impairment of
systolic function was greater in the male population.

Hence, females seem less likely to have systolic dysfunction as the principal cause for their heart failure symptoms. This appears to be compatible with the finding that
males more frequently had evidence of ischaemic heart
disease and previous myocardial infarction.
Few and mostly smaller studies of patients with stable
CHF (i.e. not immediately post MI) have previously
addressed the issue of gender related differences in LV
systolic function. In a population of 557 consecutive
patients with severe heart failure referred to a specialized heart failure clinic, Adams et al found a higher
ejection fraction in women, whereas no significant difference in end-diastolic diameter was detected.4 This is
supported by data obtained both in a community setting27 and in hospitalized patients.28,29 In contrast, two
studies of patients with severe LV dysfunction enrolled in
a clinical trial or referred for invasive evaluation have not
reported gender related differences in ejection fraction.5,8 From pathophysiological studies in humans as
well as in laboratory animals it is known that females
adapt to pressure overload with a greater degree of
concentric hypertrophy than male individuals. In contrast
the left ventricle in males is prone to dilation and progressive impairment of contractile properties.30,31 Thus
at least for the patients with heart failure due to
hypertension, experimental data are in line with the
findings of the present study. Based on the epidemiological data it seems reasonable to say that in unselected

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History of:
IHD
Angina pectoris
MI
Hypertension
Valve disease
Smoking
COPD
Diabetes
Atrial fibrillation

Males (n=1508)a

Sex and prognosis in heart failure

heart failure patients a greater degree of preserved LV

systolic function and diastolic dimensions is to be
expected in the female population.
Previous studies have raised the concern that women
with heart failure are treated less intensively with documented life saving intervention than men.32 In the
present study this hypothesis could be confirmed with
regard to ACE inhibitor therapy at discharge. Adding to
that, it has been shown that ACE inhibitor therapy is more
frequently discontinued in females,33 implying that the
true difference in treatment rates could be substantial
for the patients in the present registry. A difference in
treatment frequency between the sexes was found in all
age groups but it was clearly greater in the elderly
patients. The reason for the lower frequency of ACE
inhibitor treatment in the elderly patients of present
study is not clear. Although renal dysfunction generally
should not preclude treatment with ACE inhibitors it may
constitute a contraindication (for instance in the case of
bilateral renal artery stenosis). In the present study renal
dysfunction was more common in women with systolic
dysfunction than in men (Table 2), and this may have
caused a lower frequency of ACE inhibitor treatment in
females. However, the number of patients with severe

renal dysfunction was low and this finding cannot

completely explain the difference in ACE inhibitor treatment, meaning that other factors must have played a
role as well. Since the data for the DIAMOND-CHF
registry were collected before the emergence of solid
documentation for mortality benefit of beta blocker
therapy in systolic heart failure, few patients in the
current cohort were treated with this class of agents.
However, recently published data have shown that beta
blocker therapy is equally effective in men and women
with heart failure.34 Therefore, the fact that the number
of patients on beta blocker therapy in the DIAMOND
CHF-registry is lower than one would expect from a
contemporary heart failure population, should not decrease the relevance of the outcome data from this
population.
The present study showed that male gender per se was
associated with a lower survival rate in patients hospitalized with heart failure. Previous studies on intermediate
or long-term (>6 months) survival in men and women
with heart failure are conflicting. Several studies have
reported a poorer outcome in men either in univariate
analyses or after controlling for the influence of covariates (particularly age).35,7,3537 In contrast, a number
of other studies have reported a higher mortality in men,
which did not persist in a multivariate analysis controlling
for one or more factors.26,38 Furthermore a number of
studies have shown no difference in mortality in univariate analysis2,812 or even higher mortality in women
as described for the patients in the SOLVD registry.13 The
reasons for the different outcomes of these analyses are
not clear, but likely candidates are differences in study
populations, especially with regards to the degree of
heart failure, exclusion of patients with non-systolic
heart failure and the prevalence of ischaemic heart
disease in the population.4 Furthermore, it should be
recognized that several of the studies cited above
included 20% females or less, which could imply that the
size of the female population was simply too small to
detect any differences in mortality. The DIAMOND registry overcomes some of these difficulties in being a consecutive database with a large number of female patients
and by having data on systolic function on almost all
individuals.
It should be noted that although ischaemic heart
disease was more common in males, ischaemic heart
disease was very frequent in the female population as
well. This may be different from other populations, for
instance afro-Americans, where hypertension may be a
leading cause of heart failure,39 which may again lead to
a different effect of sex on the survival pattern. Therefore, the results of the present analysis may only be
applicable to a Caucasian population.
It is important to underline that although the current
analysis shows that women with heart failure have a
superior prognosis to that of men of comparable age, the
life expectancy of females with heart failure is much
reduced. The median survival time for the women in the
DIAMOND CHF registry was 1364 days or less than 4 years.
In comparison the expected lifetime for women aged
74 years in Denmark is more than 12 years.

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Fig. 1 Mortality rate in 2189 women and 3302 men hospitalized with
congestive heart failure (Log rank: ns).

133

134

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The mechanism behind the difference in mortality in

men and women with CHF is not clear. Most previous
studies addressing this issue have focused on differences
in the change in LV geometry and function in CHF in the
two sexes as previously discussed. In the present study,
the poorer survival in men was not merely a consequence
of a lower LVEF in the male population since this was
corrected for in the multivariate model. Others have
suggested that a higher prevalence of myocardial
ischaemia in the male population might be responsible
for the difference in outcome.4 In our study the mortality
difference between men and women persisted even if
history of ischaemic heart disease and previous MI
were added to the model, which would argue against
ischaemia as a principal explanation. However,
ischaemia was presumable under-diagnosed and therefore this conclusion may not necessarily be correct. Possibly, a greater understanding of the difference may come
from molecular studies, some of which have recently
shown that myocyte apoptosis is increased in female
patients with CHF.40 It seems clear, however, that further studies are required to shed light on the mechanism
behind the unequal outcome in male and female heart
failure patients.
In conclusion, it seems reasonable to state that in a
population with a relatively high prevalence of ischaemic
heart disease in both sexes, female gender per se is
associated with a better long-term survival in hospitalized patients with CHF. This finding obviously implies
that an effort should be made to improve prognosis in the
male CHF population. However, it certainly should not
remove the attention from a potential under-treatment
of women with CHF, who even if their prognosis is
superior to that of men, still face a substantial reduction
in life expectancy.

F. Gustafsson et al.

Sex and prognosis in heart failure

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