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European Journal of Heart Failure 2008 10(2):140-148; doi:10.1016/j.ejheart.2007.12.012
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© 2008 European Society of Cardiology

Gender related differences in patients presenting with acute heart failure. Results from EuroHeart Failure Survey II

Markku S. Nieminena,*, Veli-Pekka Harjolaa, Matthias Hochadelf, Helmut Drexlerd, Michel Komajdag, Dirk Brutsaertb, Kenneth Dicksteinc, Piotr Ponikowskii, Luigi Tavazzij, Ferenc Follathe and Jose Luis Lopez-Sendonh

a Division of Cardiology, Department of Medicine, Helsinki University Central Hospital Finland
b Department of Cardiology, A.Z Middelheim Hospital, University of Antwerp Belgium
c University of Bergen, Cardiology Division, Stavanger University Hospital Norway
d Helmut Drexler, Abt. Kardiologie u. Angiologie, Zentrum Innere Medizin, Med. Hochschule Hannover (MHH) Germany
e Department of Internal Medicine, University Hospital Zurich Switzerland
f Institut für Herzinfarktforschung Ludwigshafen an der Universität Heidelberg Germany
g Cardiology Department, CHU Pitie Salpetriere Paris, France
h Department of Cardiology — Planta 1, Hospital Universitario La Paz Madrid, Spain
i Department of Cardiology, Military Hospital Wroclaw, Poland
j Luigi Tavazzi, Divisione di Cardiologia, Policlinico san Matteo, I.R.C.C.S Pavia, Italy

* Corresponding author. Division of Cardiology, Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, POB 340, 00290 Helsinki, Finland. Tel.: +358 9 47172200; fax: +358 9 47174015. E-mail address: markku.nieminen{at}hus.fi (M.S. Nieminen).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Aims: This analysis evaluates the gender differences in patients hospitalised for acute heart failure (AHF) in the EuroHeart Failure Survey II (EHFS).

Results: Of the 3580 patients included in EHFS II, 1384 (39%) were women, mean age 73 years. 2196 (61%) were men, mean age 68 years. Women more frequently had new-onset AHF, hypertension and valvular disease and less frequently coronary heart disease or dilated cardiomyopathy compared with men. Smoking, chronic obstructive pulmonary disease, peripheral arterial disease and renal failure were less common, but diabetes and anaemia significantly more frequent in women. Atrial fibrillation and preserved left ventricular function were more common in women. Men were more often non-compliant with medication. After adjustment for indications and age, there were no significant gender differences in prescription of HF medication.

All-cause readmission rate during the one-year follow-up was lower in women. However, the proportion of HF hospitalisation and one-year mortality after discharge (20%) were similar in both genders.

Conclusion: Women frequently present with new-onset AHF. A significant gender difference exists in aetiology, ventricular function and co-morbidities. Women's use of HF medication has improved. These findings emphasize the importance of individualised management and need for more comprehensive recruitment of women in clinical trials.

Key Words: Acute heart failure • Demographics • Echocardiography • Gender • Medication • Prognosis

Received April 19, 2007; Revised November 4, 2007; Accepted December 20, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
The prevalence of heart failure (HF) in an unselected population over 45 years of age is estimated to be 2.2% and in a population over 65 years of age 8.8% [1,2]. Acute heart failure (AHF) is said to be the most frequent cause of admission to emergency wards and the most costly [3]. With the ageing of the population the impact of heart failure on health care resources is increasing. Importantly, in the elderly population the proportion of women is substantially greater.

In chronic HF, the proportions of systolic HF and HF with preserved left ventricular ejection fraction are relatively similar in the whole HF population. However, the prevalence of preserved LVEF exceeds that of systolic dysfunction in the elderly and in female HF patients [2,4]. Other differences in HF between women and men exist as well. Coronary artery disease is less frequently the underlying aetiology in women, while hypertension is a prominent cause [5,6]. Despite the older mean age of female HF patients, their age-adjusted prognosis is better than the prognosis of male patients [6-9].

There are few reports on the incidence and characteristics of acute HF in women. In the previous EuroHeart Failure Survey, 47% of patients were female [10] and they received appropriate HF medication less often than male subjects [11]. Furthermore, the proportion of female subjects has ranged from none to 40% in randomised clinical trials on chronic HF, and it has been 30% or less in AHF trials [12]. Thus, women have been clearly under-represented in these trials. Some data demonstrate that even echocardiography is less often performed in female patients and they are less often followed-up at hospital outpatient clinics [6,13].

Discharge codes usually detect the diagnosis of HF in patients with chronic decompensated heart failure effectively, but patients with acute "de novo" heart failure are frequently missed in registry based studies [14]. It is therefore important to collect data about AHF patients from prospective surveys. The EuroHeart Failure Survey II on acute heart failure (EHFS II) [15] provides a database that permits analysis of heart failure hospitalisations as classified in the recent ESC guidelines on AHF [16]. This analysis evaluates the gender related differences in patients hospitalised for AHF with respect to the demographics, underlying aetiology, co-morbidities, and type of AHF, as well as management and clinical course.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Materials and methods
The database was collected electronically according to the EuroHeart survey study plan, as previously reported [15]. In brief, patients were screened in the emergency area, including cardiac care (CCU) and intensive care (ICU) units, and internal medicine and cardiology wards of the 133 participating hospitals. University hospitals accounted for 47% of the hospitals, 49% were community or district hospitals and 4% were private clinics in 30 European countries. The recruitment lasted 10 months, from October 21st 2004 until August 31st 2005. The patients were followed-up at 3 months and 1 year after inclusion.

2.1.1. Inclusion criteria
The EuroHeart Failure Survey II recruited patients admitted to hospital with dyspnoea and verified heart failure based on a) clinical symptoms (dyspnoea) and signs of heart failure (i.e. rales, hypotension, hypoperfusion) and b) signs of heart failure on chest X-ray.

2.1.2. Classification of included patients
The patients were classified according to the guidelines on acute heart failure of the ESC by the attending physician. Acute decompensated chronic heart failure (ADCHF) was defined as worsening of heart failure in patients with a previous diagnosis or hospitalisation for heart failure or as new-onset acute heart failure ("de novo" AHF) for patients with no prior history of heart failure. The severity and pattern of the acute heart failure were assessed as described previously [15].

Clinical history, symptoms and signs, and medication (at admission as well as at discharge) were recorded. Coronary artery disease was defined as verified patient history with concurrent anti-anginal medication or history with positive exercise test nuclear scans, angiography, revascularization or myocardial infarction. History of atrial fibrillation included paroxysmal, persistent and permanent atrial fibrillation. Valvular disease was defined as presence of any regurgitation or gradient over a valve with haemodynamic significance and/or related symptoms. Diabetes was defined as fasting blood glucose ≥6.5 mmol/l or treatment with oral hypoglycaemic agent and/or insulin. Chronic renal failure was defined as a history of renal failure documented by any of the following: (a) current or previous serum creatinine chronically greater than177 µmol/l, (b) patient on dialysis, (c) history of renal transplantation. Any other concomitant or underlying diseases were recorded as described in the patient's medical history (chronic obstructive pulmonary disease (COPD), thyroid disease etc). The most recent echocardiography data was collected. Diastolic dysfunction was classified by the investigator as mild, moderate or severe according to generally accepted echocardiographic criteria [17].

2.1.3. Statistical analysis
The dataset is 99% complete for the main variables. The data are presented as numbers and percentages, and medians with interquartile range (IQR), as appropriate. For age and ejection fraction, means and standard deviations are given. The distribution of dichotomous baseline variables was compared between genders by chi-square test and odds ratios with 95%-confidence intervals were calculated. With respect to ordinal categorical variables the genders were compared by Cochran-Armitage test and cumulative odds ratios are shown comparing the more diseased vs. the less diseased categories for different cut-points. Comparisons with respect to continuous variables were done by Mann-Whitney U-test. For binary outcomes and the use of treatments, adjusted odds ratios with confidence intervals were calculated by multiple logistic regression. The comparison of mortality after discharge was adjusted for age by Cox regression including age as a linear term. As no significant age by gender interaction was found (p=0.32), a stratified Cox model was used to compute expected survival curves for given age values by the product-limit method. Rehospitalisation rates were calculated as the number of rehospitalisations divided by person-months under observation, and age-adjusted rate ratios were estimated by negative-binomial regression in order to account for possible overdispersion. The inclusion of covariates in the models resulted in a loss of less than 0.5% of the patients due to missing values.

A significance level of 0.05 was assumed and all P-values are the results of two-tailed tests. The statistical computations were performed using SAS, version 9.1 (Cary, North Carolina, U.S.A.).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Baseline characteristics and clinical class of AHF patients by gender
The EHFS II collected data from 3580 AHF patients of which 1384 (38.7%) were female. The baseline characteristics are reported in Table 1. The female AHF patients were older, more often retired, living alone or in special accommodation. The age distribution of male and female patients is presented in Fig. 1 which shows the rightward shift towards older age groups in the female patients as compared with the male patients. Of the underlying cardiovascular conditions, women more often had hypertension, valvular disease, atrial fibrillation or flutter and less frequently had coronary heart disease, dilated cardiomyopathy and peripheral arterial disease as compared with male subjects. Regarding important co-morbidities, women more often had diabetes, anaemia and thyroid diseases, but less often had chronic obstructive pulmonary disease (COPD), renal failure or were smokers.


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  		Table 1 Baseline characteristics of all EuroHeart Failure Survey II patients and by gender

 


Figure 01
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  		Fig. 1 Relative age distribution for female and male patients. Data are shown in percentages from each gender.

 
New-onset AHF was significantly more common in female patients (41%) than in male subjects (35%). Clinical classification according to the guidelines divided the female and male AHF patients as follows: decompensated heart failure (64% and 66%), pulmonary oedema (17% and 16%), hypertensive heart failure (12% and 11%), cardiogenic shock (3% and 4%) and right heart failure (4% and 3%), respectively. None of these gender differences were significant.

3.2. Precipitating factors for acute heart failure hospitalisation
The precipitating factors for HF hospitalisation differed between female and male patients. Women more often presented with atrial arrhythmia and men with ventricular arrhythmias. Valvular heart disease was more common in women. Men were more often hospitalised due to lack of compliance with medication than women (Table 2). The prevalence and distribution of acute coronary syndromes were similar in men and women (Table 2).


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  		Table 2 Precipitating factors of heart failure on admission

 
3.3. Clinical and echocardiographic findings
The median systolic blood pressure on admission was higher in women (Table 1). Women less often had left bundle branch block (17% vs. 24% in men P<0.001) and pathological Q waves on the ECG (23% vs. 32% in men, P<0.001). QRS duration was 100 ms (IQR 89-120) in female patients as compared with men with 108 ms (90-130, P<0.001).

Echocardiography results were available in the majority of patients enrolled in EHFS II (Table 3), and left ventricular ejection fraction (LVEF) was reported in 89% of patients (2733/3062). Transthoracic or transoesophageal echocardiography was performed during hospitalisation or within one-year of admission slightly more often in men than in women. Of the echocardiograms, 85% were performed during the index hospitalisation. Median left ventricular end-diastolic diameter was smaller in women; in addition, mild as well as severe systolic LV failure was less common in women. Accordingly, a LVEF of ≥45% was present significantly more often in women. Diastolic dysfunction was very frequent. Severe diastolic dysfunction, as classified by the investigator, was more prevalent in the male subjects. Likewise, right ventricular dilation and dysfunction was reported more often in men.


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  		Table 3 Echocardiographic findings

 
Valvular disorders were commonly reported in the echocardiograms. The most frequent was moderate to severe mitral regurgitation (MR) which was reported in 43% of the study population with no gender related differences. Moderate to severe tricuspid regurgitation was reported more often in female patients. Similarly, moderate to severe aortic stenosis was more common in female patients.

3.4. Procedures and treatment
BNP and NT-proBNP measurements were recorded in only 16% of the study population regardless of gender. There were no significant gender related differences during hospitalisation in echocardiography or other investigations like magnetic resonance imaging, electrophysiological testing or monitoring with an arterial line or a pulmonary artery catheter (Table 4). Pulmonary artery catheter was used for hemodynamic guidance in 5% of the overall patient population, but in 25% of patients in the cardiogenic shock group. The only significant gender related differences were observed in the use of coronary angiography, Holter monitoring and exercise testing which were performed significantly more often in the male subjects.


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  		Table 4 Investigations and procedures performed during hospitalisation

 
There were no gender related differences in the use of a continuous positive airway pressure mask (CPAP) or mechanical ventilation. However, inotropic agents, more specifically dobutamine (8.3% vs. 11.3% in women and men, respectively), dopamine (9.5% vs. 12.4%) and levosimendan (2.2% vs. 4.9%), as well as, placement of an intra-aortic balloon pump (1.6% vs. 2.6%) were less often prescribed to female patients than to the male patients. Intravenous amiodarone was also less commonly used in women. Thrombolytic therapy and coronary angiography were performed less often in women. Women received blood transfusions more often than men. However, the transfusions were indicated because of bleeding more often in men than in women. Heart transplantation was performed at similar rates between the genders.

3.5. Cardiovascular medication
Admission and discharge medications are listed in Table 5. Aldosterone antagonists, anti-arrhythmic drugs, aspirin and lipid lowering drugs were less frequently prescribed to women, whereas they more often received calcium channel blockers, digoxin and insulin at admission. However, after adjustment for clinically significant covariates (age, history of CHD and CHF, known systolic dysfunction and atrial fibrillation) there were no statistically significant differences in prescribing cardiovascular medication to women as compared with men. The prescription rate of all cardiovascular medications increased from admission to discharge with the exception of calcium channel blockers which were prescribed less often at discharge.


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  		Table 5 Medication on admission to hospital and at discharge

 
3.6. In-hospital mortality and length of stay
In-hospital mortality was 6.6% in all patients without any significant difference between the genders. Similar proportions of male and female patients were treated in intensive care or cardiac care units, as well as, in the internal medicine and cardiology wards. There were no differences in the length of stay in different facilities. Median length of stay (LOS) was 9 days (IQR 6-14) for both genders (Table 6). There was no gender difference in the incidence of major cardiovascular events during hospitalisation and follow-up (death, myocardial infarction or stroke).


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  		Table 6 Length of stay, discharge status and major complications during index hospitalisation

 
3.7. Rehospitalisations and one-year mortality
Follow-up data at three months (median 100, IQR 92-117 days) and one-year (median 372, IQR 361-397 days) were available in 2981 and 2301 patients, respectively. In the first 3 months after discharge from hospital, 462 all-cause readmissions were observed in women during 3455 person-months under observation (0.134 per person-month), as compared with 884 readmissions during 5603 person-months (0.158 per person-month) in men. Negative-binomial regression yielded an age-adjusted rate ratio of 0.84 (95%-CI 0.74-0.96). However, there was no gender difference in the proportion of rehospitalisations for HF which accounted for 60.3% of all readmissions in women and for 61.5% in men. All-cause readmission rates between 3 months and one year were 587/7458 months (0.079/month) in women and 1063/11,838 months (0.090/month) in men, with an age-adjusted rate ratio of 0.84 (0.73-0.97). The proportion of HF admissions was similar to the first 3-month period. There was no gender related difference in cumulative one-year mortality which was 20% in both men and women. Expected survival curves for patients aged 60 and 80 years are shown in Fig. 2. The percentage of nights that were spent in hospital from discharge to 3 months was 4.1% for women as compared with 4.6% for men, and from 3 months to 1 year 2.4% vs. 2.5%.


Figure 02
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  		Fig. 2 Expected survival curves for 60 and 80 year old men and women hospitalised for acute heart failure. The curves for the two age groups are based on a common stratified Cox model and similar in shape. Women are shown in dotted lines and men in solid lines.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The present study is the first to analyse the characteristics of female and male patients hospitalised for acute heart failure. The present data demonstrate many important gender differences in a large European population of AHF patients. Female patients are on average 6 years older than male patients at admission. Although chronic heart failure is usually thought to be more prevalent in the elderly, the female subjects despite their higher age at admission more often present with "de novo" AHF than male subjects. The spectrum of underlying cardiovascular diseases as well as co-morbidities is also different between the genders. One major difference is history of smoking which is reflected by a higher incidence of COPD in male than in female subjects. Although acute coronary syndrome is equally common in female and male patients, women undergo coronary angiography less often. Interestingly, after adjustment for clinically significant covariates there were no statistically significant differences in prescribing cardiovascular medication to women as compared with men.

The proportion of female patients was smaller in the present survey as compared with EHFS I [10]. Moreover, in a US registry, more women than men were hospitalised with AHF [18]. Female patients with AHF in the present study were older than males, as has been shown before [9,18]. In the ADHERE registry, the mean age of women and men was slightly higher than in the present survey [18]. Interestingly, in the present study, de novo heart failure was more common in female patients. This may reflect the rapidly increasing incidence of heart failure in elderly patients as compared with middle-aged patients.

The present data confirm the reports in the literature on gender differences in underlying diseases. As shown in chronic HF, hypertension was the most common underlying cardiovascular disease in female AHF patients. Coronary heart disease and dilated cardiomyopathy were less common in women than in men as has been shown previously [9,18,19]. In men, coronary heart disease and hypertension were equally prevalent, and were the leading underlying diseases. The significantly higher prevalence of history of valvular heart disease and atrial fibrillation and flutter and lower prevalence of dilated cardiomyopathy in women than in men is compatible with previous reports [19]. In the DIAMOND study, a history of valvular disease was also significantly more common in women than men, but with a markedly lower prevalence than in this survey [9].

Men are more often cigarette smokers than women. This is reflected to the higher prevalence of COPD, peripheral arterial disease and coronary heart disease in men. Renal failure, an important prognostic factor, was also more common in men. These findings are compatible with recent data [18,19]. In contrast to ADHERE, but in line with recent Italian data, women in EHFS II had diabetes and anaemia more often than men [18,19].

Although Holter monitoring, exercise testing and coronary angiography were more frequently performed in men, there were less differences in the use of invasive and non-invasive investigations during hospitalisation than might have been expected in light of the previous literature [6,13,19]. Echocardiography was performed equally often in both genders. As expected, preserved LVEF was observed twice as often in women than in men. In a recent paper, up to 73% of patients hospitalised for heart failure with a normal ejection fraction were female [20]. The higher prevalence of preserved LVEF in females is associated with hypertension and older age. However, diastolic dysfunction was reported very frequently in both genders in this survey. Moderate to severe tricuspid regurgitation and aortic stenosis were also more often observed in the female patients.

Differences in concomitant diseases influence the use of cardiovascular medication. The higher use of digoxin on admission in women reflects the higher prevalence of atrial fibrillation and flutter. In men, the use of aspirin and lipid lowering drugs reflects the higher prevalence of coronary artery disease. However, after adjustment for clinically significant covariates there were no statistically significant differences in prescribing cardiovascular medication to women as compared with men. In previous reports female patients have received ACE inhibitors and aldosterone antagonists less often than men [6,9,19,21]. The same observation was made regarding beta blockers in the first EuroHeart Failure Survey [11] but not in all populations [19]. These findings likely reflect the smaller proportion of systolic HF and the higher proportion of de novo HF in women. In addition, a more cautious prescribing policy may have reasonably been employed in the eldest patients. The IMPROVEMENT study showed that if systolic dysfunction was documented, primary care physicians were more likely to prescribe ACE inhibitors but less likely to prescribe beta blockers [22]. Encouragingly, the use of recommended medication for CHF has increased since the first EHFS [11]. The prescription rate of all cardiovascular medications increased from admission to discharge with the exception of calcium channel blockers which were prescribed less often.

It is noteworthy that there were no differences in the prevalence of ACS, or its subclasses STEMI, NSTEMI and unstable angina, between male and female patients, despite the significantly higher prevalence of coronary heart disease in men. However, women underwent significantly fewer invasive procedures as well as thrombolytic therapy. This contradictory finding is in line with a recent gender analysis from the CURE study [23], but in contrast to Swedish data which did not show any gender differences [24]. An analysis from the National Hospital Discharge Survey on patients with heart failure as a first-listed diagnosis confirmed that men were twice as likely to undergo invasive cardiac procedures as were women during hospitalisation in the United States between 1985 and 1995 [25]. Likewise, in the ADHERE registry, women consistently received less procedure-oriented therapy [18]. However, the less aggressive approach in treatment of ACS in female patients in EHFS II was not reflected in the use of other investigations and invasive monitoring, in which no gender differences were observed. However, inotropic agents as well as intra-aortic balloon pumps were less often prescribed to female than male patients.

Despite the older age of the female patients, there were no gender differences in the in-hospital mortality, major cardiovascular events or length of stay. This is in line with ADHERE data [18]. Expected survival was slightly better for 60 and 80 year old women than men, but the difference was not statistically significant. Similarly, a better survival rate in women has been reported by others, at least when adjusted for age [6,9]. Both genders were treated as frequently and as long in the different types of wards (internal medicine, cardiology, ICU and CCU).

The rehospitalisation rates during the one-year follow-up period are described. It is striking that although women were older they were less often hospitalised for any cause during the one-year follow-up period. Still, the proportion of nights spent in hospital was similar in men and women, reflecting longer lengths of stay in hospital for women. The majority of hospitalisations were due to HF in both genders.

4.1. Limitations of the study
The voluntary basis of participation and recruitment of patients into this study presents certain limitations. There was no formal audit on data quality either. However, all the centres had participated in the EuroHeart program previously and therefore had experience in performing a survey. The patients were recruited mainly from larger hospitals which may cause a bias toward better implementation of evidence based therapy and use of diagnostic procedures. Some large Central European countries did not participate in the survey.

The possibility of generalizing the results from a survey is never inclusive, and the data are representative for the participating centres only. Predefined criteria aimed at identifying patients with verified AHF, but the final diagnosis was not confirmed centrally. The clinical classification was also assessed locally. Furthermore, there was no centralized reading of echocardiographic results.

The interpretation of use of recommended heart failure therapy and treatment for ACS is limited by the fact that reasons for not prescribing heart failure medication and thrombolysis, as well as, invasive treatment of ACS were not recorded.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In many aspects, the female and male patients presenting with AHF represent two different clinical constellations. Women present with hypertension, valvular diseases, supraventricular arrhythmias and preserved LV function more often than men. Male patients are younger, more often cigarette smokers and have coronary heart disease and dilated cardiomyopathy. Women more frequently have diabetes, anaemia and thyroid disease, whereas men more often have renal failure, peripheral arterial disease and COPD. These findings emphasize the importance of individualised management and underscore the need for more comprehensive recruitment of women in clinical trials. Although the data from this survey do not provide an insight into the reasons for the observed differences in management, there is likely room for improvement in the management of female patients with ACS and AHF. Encouragingly, the prescription rate of heart failure medication has improved and the gender differences in medication have disappeared since the previous EuroHeart Survey in Europe.


   Acknowledgements
 
We acknowledge the following companies who have supported the study. Main sponsors: Abbott Laboratories, GlaxoSmithKline Services Unlimited, Roche Diagnostics GmbH and Sanofi-Synthelabo Groupe. EuroHeart Failure Survey II was endorsed by the Heart Failure Association of the European Society of Cardiology, formerly the Working Group on Heart Failure.

The organization of the EuroHeart Failure Survey II, including a list of Participating Centres, Investigators, and Data Collection Officers, has been reported previously [15].


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

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