Abstract
Background
Heart failure (HF) differs in many ways between women and men.
Aim
To determine predictors of outcomes in women with HF.
Methods
We performed a retrospective follow up study of women with HF who participated in the Digitalis Investigation Group (DIG) trial. Using multivariable Cox proportion hazard models we identified independent predictors for all-cause mortality, hospitalization due to worsening HF, and all-cause hospitalization.
Results
In the DIG trial, 24.7% participants (1926/7788) were women whose mean (±SD) age was 65.5 (±11.9) years, 18.4% (354/1926) were nonwhite, and 21.1% (407/1926) had a left ventricular ejection fraction (LVEF) >45%. Adjusted hazard ratios and 95% confidence intervals for covariates that were significant independent predictors of all-cause mortality were: age in years (1.02; 1.01 – 1.03; p<0.001), NYHA class III-IV (1.56; 1.31 – 1.87), diabetes (1.63; 1.36 – 1.95), glomerular filtration rate in ml/min/1.73 meter2 (0.99; 0.98 – 0.996; p=0.001), pulmonary congestion by chest x-ray (1.57; 1.22 – 2.02), LVEF (0.99; 0.98 – 0.993; p<0.001) and use of digoxin (1.20; 1.02 – 1.42). Covariates that were significant independent predictors of hospitalization due to worsening heart failure were: non-white race (1.28; 1.03 – 1.58), NYHA class III-IV (1.55; 1.30 – 1.84), diabetes (1.75; 1.47 – 2.09), glomerular filtration rate as ml/min/1.73 meter2 (0.99; 0.986 – 0.996; p<0.001), pulmonary congestion by chest x-ray (1.42; 1.12 – 1.81), and use of ACE inhibitors (0.67; 0.49 – 0.91).
Conclusion
Longer duration of HF, higher NYHA classes, diabetes, chronic kidney disease, pulmonary congestion and lower LVEF were significant independent predictors of all-cause mortality, all-cause hospitalization, and hospitalization for heart failure in women with HF.
Keywords: digoxin, heart failure, outcomes, women
1. Introduction
Heart failure differs in many ways between genders. Women with heart failure are generally older than men, more likely to have preserved left ventricular systolic function [1-5] and have lower mortality [6-9]. Compared with men, women with diabetes and hypertension, and after myocardial infarction are at higher risk of developing heart failure [10, 11]. The age-adjusted rates for hospitalizations due to heart failure has increased significantly in the past decade for women, but not for men [12]. The risk of hospitalization and re-hospitalization for women with heart failure have been described as higher than or similar to those in men [7, 13]. Use of digoxin has been shown to be associated with a significant increased risk of death in women with heart failure and a left ventricular ejection fraction of 45% or less [14]. The objective of this study was to determine predictors of all-cause mortality, hospitalization due to worsening heart failure and all-cause hospitalization in ambulatory women with chronic heart failure across a broad range of ejection fraction.
2. Methods
2.1. Subjects
The subjects of this study are 1,926 women who participated in the DIG trial. The trial involved 6,800 patients with systolic heart failure (ejection fraction ≤ 45%) and 988 with diastolic heart failure (ejection fraction > 45%).
2.2. Data Source
The public use version of the DIG dataset was obtained from the National Heart, Lung and Blood Institute after an expedited review was approved by the Institutional Review Board of the University of Alabama at Birmingham. All patients provided signed informed consent forms during the main trial, and the original protocol was approved by the Institutional Review Boards of all the participating centers.
2.3. Study Design
This is a retrospective follow up study of women who participated in the DIG trial. The details of the design of the DIG trial have been reported [15, 16]. The DIG trial was a prospective, randomized, double-blind placebo-controlled clinical trial that enrolled 7,788 ambulatory patients with chronic systolic heart failure patients at 302 clinical centers in the United States and Canada. Patients were randomized to receive digoxin or placebo. Most patients were receiving angiotensin-converting enzyme (ACE) inhibitors and diuretics. Data on beta blockers and aldosterone antagonists were not collected.
2.4. Study Outcomes
Outcomes of interest for the present analysis included all-cause mortality, hospitalization due to worsening heart failure, and all-cause hospitalization over the mean follow-up of 37 months (range 28 to 58 months).
2.5. Statistical Analysis
We compared baseline characteristics among patients randomized to digoxin versus placebo and tested statistical significance using Pearson Chi-square tests and Student’s t tests as appropriate. Because the balance in baseline covariates achieved during randomization in the original trial might have been disrupted in the subgroup of our current study, we estimated propensity scores for the receipts of ACE inhibitors, and matched patients based on propensity scores. There was no difference in baseline covariates between the groups before or after propensity score matching. Therefore, all subsequent analyses were based on all women, and on those matched by propensity scores. Next, we used multivariable Cox proportional hazard regression analyses to estimate risk of all-cause mortality, all-cause hospitalization and heart failure related hospitalization. Covariates used in the multivariable Cox regression model included age, sex, race, duration heart failure in months, etiology of heart failure i.e. ischemic, hypertensive, idiopathic, and others, comorbidities i.e. myocardial infarction, current angina, hypertension, and diabetes, medications i.e. ACE inhibitors, and non-potassium sparing diuretic, New York Heart Association (NYHA) functional class, jugular venous distension, third heart sound, pulmonary râles, and lower extremity edema, and pulmonary congestion by chest x-ray, glomerular filtration rate in ml/min/1.73 meter2 as determined by the Dietary Modification in Renal Disease formula,[17] serum potassium level, and left ventricular ejection fraction. We also conducted subgroup analyses to determine the effects of digoxin on all-cause mortality. All statistical tests were done using an intention to treat approach with two-tailed 95% confidence intervals (CI), and a p < 0.05 was required to reject the null hypothesis. Analyses were performed using SPSS for Windows (Release 12.02) [18].
3. Results
3.1 Patient characteristics
Patients (N=1,926) had a mean (±SD) age of 65.5 (±11.9) years, 18.4% were non-white and 21.1% had an ejection fraction greater than 45%. Nine hundred sixty two (49.9%) were receiving digoxin while 964 (50.1%) were receiving placebo. Five hundred sixty nine (29.5%) patients died from all causes, 1,260 (65.4%) were hospitalized from all causes, and 599 (31.1%) were hospitalized due to worsening heart failure. Table 1 demonstrates that there was reasonable balance in patient characteristics between the digoxin and placebo groups at randomization. However, women receiving digoxin were more likely to have symptoms and signs of heart failure. In the propensity score matched cohort, there were no significant differences in baseline covariates between the two treatment groups.
Table 1.
Baseline characteristics in ambulatory women with heart failure
| Placebo (n=964) | Digoxin (n=962) | P value | |
|---|---|---|---|
| Age (years) | 65.5±11.6. | 65.5±12.2 | 0.970 |
| Nonwhite | 179 (18.6%) | 175(18.2%) | 0.831 |
| Duration of heart failure (months) | 26.5±30.6 | 26.4±26.4 | 0.956 |
| Heart failure due to ischemic heart disease | 558 (57.9%) | 577 (60.0%) | 0.350 |
| Prior myocardial infarction | 483 (50.1%) | 498 (51.8%) | 0.465 |
| Current angina pectoris | 284 (29.5%) | 269 (28.0%) | 0.467 |
| Diabetes mellitus | 335 (34.8%) | 315 (32.8%) | 0.352 |
| Systemic hypertension | 535 (55.5%) | 555 (57.7%) | 0.331 |
| Angiotensin-converting enzyme inhibitors | 894 (92.7%) | 895 (93.0%) | 0.800 |
| Prior digoxin use | 414 (43.0%) | 421 (43.8%) | 0.732 |
| Diuretics | 807 (83.7%) | 812 (84.4%) | 0.677 |
| Potassium sparing diuretics | 77 (8.0%) | 85 (8.8%) | 0.502 |
| Dyspnea at rest | 709 (73.5%) | 744 (77.3%) | 0.053 |
| Elevated jugular venous pressure | 491 (50.9%) | 537 (55.8%) | 0.032 |
| Pulmonary râles | 710 (73.7%) | 748 (77.8%) | 0.036 |
| Lower extremity edema | 176 (23%) | 97 (45%) | <0.001 |
| Blood pressure, systolic (mm Hg) | 130±22 | 131±22 | 0.570 |
| Blood pressure, diastolic (mm Hg) | 75±15 | 75±12 | 0.666 |
| Pulmonary congestion on chest x-ray | 681 (70.6%) | 720 (74.8%) | 0.038 |
| Glomerular filtration rate (ml/min/1.73 meter2) | 58.48 ±30.91 | 58.63±21.00 | 0.903 |
| Serum potassium (mEq/l) | 4.30±0.40 | 4.30±0.44 | 0.400 |
| Left ventricular ejection fraction (%) | 35.8±14 | 35.0±14 | 0.823 |
3.2 Predictors of all-cause mortality
Independent predictors for all-cause mortality in these ambulatory women with heart failure (Table 2) included age (adjusted hazard ratio, 1.02; 95% CI 1.01 – 1.03; p < 0.001), duration of heart failure (adjusted hazard ratio, 1.003; 95% CI1.001 – 1.005; p = 0.017), NYHA functional class III-IV (adjusted hazard ratio, 1.56; 95% CI 1.31 – 1.87; p < 0.001), presence of diabetes (adjusted hazard ratio, 1.63; 95%CI, 1.36 – 1.95; p < 0.001), diastolic blood pressure (adjusted hazard ratio, 0.990; 95%CI, 0.981 – 0.999; p = 0.029), glomerular filtration rate (adjusted hazard ratio, 0.986; 95%CI 0.979 – 0.996; p = 0.0001), pulmonary congestion by chest x-ray (adjusted hazard ratio, 1.57; 95%CI 1.22 – 2.02; p < 0.001), left ventricular ejection fraction (adjusted hazard ratio, 0.986; 95% CI 0.979 – 0.993; p < 0001), and digoxin use (adjusted hazard ratio, 1.20; 95% CI 1.02 – 1.42; p = 0.032).
Table 2.
Predictors for all-cause mortality in ambulatory women with heart failure
| Hazard Ratio* | 95% Confidence Intervals | P Value | |
|---|---|---|---|
| Age (years) | 1.02 | 1.01 - 1.03 | <0.001 |
| Race (nonwhite) | 1.12 | 0.88 - 1.41 | 0.364 |
| Duration of heart failure (months) | 1.003 | 1.001 – 1.005 | 0.017 |
| New York Heart Association (class III-IV) | 1.56 | 1.31 – 1.87 | <0.001 |
| Diabetes mellitus | 1.63 | 1.36 – 1.95 | <0.001 |
| Use of ACE inhibitors | 0.76 | 0.56 – 1.05 | 0.093 |
| Use of digoxin | 1.20 | 1.02 – 1.42 | 0.032 |
| Diastolic blood pressure (mm mercury) | 0.990 | 0.981 – 0.999 | 0.029 |
| Glomerular filtration rate (ml/min/1.73 meter2) | 0.991 | 0.981 – 0.996 | 0.001 |
| Pulmonary congestion (by chest x-ray) | 1.57 | 1.22 – 2.02 | <0.001 |
| Left ventricular ejection fraction (%) | 0.986 | 0.979 – 0.993 | <0.001 |
Other covariates in the multivariable Cox regression model included etiology of heart failure, past myocardial infarction, current angina, hypertension, diuretic use, heart rate, systolic blood pressure, jugular venous distension, third heart sound, and lower extremity edema, and serum potassium level.
3.3 Predictors of hospitalization due to worsening heart failure
Independent predictors for hospitalization due to worsening heart failure (Table 3) included non-white race (adjusted hazard ratio, 1.28; 95% CI 1.03 – 1.58; p = 0.024), duration of heart failure (adjusted hazard ratio, 1.003; 95% CI 1.001 – 1.005; p = 0.028), NYHA class III-IV (adjusted hazard ratio, 1.55; 95% CI 1.30 – 1.84; p < 0.001), diabetes (adjusted hazard ratio, 1.75; 95% CI 1.47 – 2.09; p < 0.001), glomerular filtration rate (adjusted hazard ratio, 0.991; 95% CI 0.986– 0.996; p = 0.0001), pulmonary congestion by chest x-ray (adjusted hazard ratio, 1.42; 95% CI 1.12 – 1.81; p = 0.004), left ventricular ejection fraction (adjusted hazard ratio, 0.986; 95% CI 0.979 – 0.992; p < 0001), and use of ACE inhibitors (adjusted hazard ratio, 0.67; 95% CI 0.49 – 0.91; p = 0.011).
Table 3.
Predictors of hospitalization due to worsening heart failure in ambulatory women with heart failure
| Hazard Ratio* | 95% Confidence Intervals | P Value | |
|---|---|---|---|
| Age (years) | 1.01 | 1.00 - 1.02 | 0.079 |
| Race (nonwhite) | 1.28 | 1.03 - 1.58 | 0.024 |
| Duration of heart failure (months) | 1.003 | 1.000 - 1.005 | 0.028 |
| New York Heart Association (class III-IV) | 1.55 | 1.30 - 1.84 | <0.001 |
| Use of ACE inhibitors | 0.67 | 0.49 - 0.91 | 0.011 |
| Use of digoxin | 0.87 | 0.74 - 1.02 | 0.083 |
| Myocardial infarction | 0.79 | 0.64 - 0.98 | 0.028 |
| Diabetes mellitus | 1.75 | 1.47 - 2.09 | <0.001 |
| Heart rate (beats per minute) | 1.008 | 1.0010 - 1.014 | 0.024 |
| Diastolic blood pressure (mm mercury) | 0.989 | 0.981 - 0.998 | 0.018 |
| Glomerular filtration rate (ml/min/1.73 meter2) | 0.991 | 0.986 - 996 | <0.001 |
| Pulmonary congestion (by chest x-ray) | 1.42 | 1.12 - 1.81 | 0.004 |
| Left ventricular ejection fraction (%) | 0.986 | 0.979 - 0.992 | <0.001 |
Other covariates in the multivariable Cox regression model included etiology of heart failure, past current angina, hypertension, diuretic use, systolic blood pressure, jugular venous distension, third heart sound, and lower extremity edema, and serum potassium level.
3.4 Predictors of all-cause hospitalization
Table 4 displays the independent predictors for all-cause hospitalization. In addition to duration of heart failure, NYHA class, use of ACE inhibitors, diabetes, diastolic blood pressure, and pulmonary congestion, angina at the time of randomization was associated with higher risk of all-cause hospitalization (adjusted hazard ratio, 1.25; 95% CI 1.10 – 1.42; p = 0.001). Age, renal function, and left ventricular systolic function were not independent predictors of all-cause hospitalization.
Table 4.
Predictors of all-cause hospitalization in ambulatory women with heart failure
| Hazard Ratio* | 95% Confidence Intervals | P Value | |
|---|---|---|---|
| Age (years) | 1.00 | 0.99 - 1.01 | 0.840 |
| Race (nonwhite) | 1.11 | 0.95 - 1.29 | 0.190 |
| Duration of heart failure (months) | 1.003 | 1.001 – 1.004 | 0.002 |
| New York Heart Association (class III-IV) | 1.36 | 1.20 - 1.53 | <0.001 |
| Use of ACE inhibitors | 0.77 | 0.62 - 0.95 | 0.015 |
| Use of digoxin | 1.00 | 0.89 - 1.11 | 0.957 |
| Angina | 1.25 | 1.10 - 1.42 | 0.001 |
| Diabetes mellitus | 1.44 | 1.27 - 2.63 | <0.001 |
| Diastolic blood pressure (mm mercury) | 0.992 | 0.986 - 0.998 | 0.008 |
| Glomerular filtration rate (ml/min/1.73 meter2) | 0.997 | 0.994 – 1.000 | 0.094 |
| Pulmonary congestion (by chest x-ray) | 1.24 | 1.06 - 1.44 | 0.006 |
| Left ventricular ejection fraction (%) | 0.999 | 0.994 - 1.003 | 0.547 |
Other covariates in the multivariable Cox regression model included etiology of heart failure, past myocardial infarction, hypertension, diuretic use, heart rate, systolic blood pressure, jugular venous distension, third heart sound, and lower extremity edema, and serum potassium level.
4. Discussion
This analysis from the DIG trial, based on a large cohort of ambulatory women with chronic heart failure from multiple centers in the US and in Canada, identified several important predictors of mortality and hospitalization. Older age, longer duration of heart failure, higher NYHA class, diabetes, lower kidney function and ejection fraction, pulmonary congestion by X-ray and digoxin use were associated with greater all-cause mortality. Most of these same variables except age and digoxin use were also predictive of all-cause and heart failure hospitalizations, ACE inhibitors were protective against these latter outcomes.
4.1 Heart failure in women
There is increasing evidence that the risk factors, pathogenesis, prognosis, and response to treatment may be different in women than in men with heart failure. Even though the incidence and prevalence of heart failure are somewhat lower in women than in men [19-21], the proportion of women with heart failure increases with age, and many of these women have preserved left ventricular systolic function [19]. The proportion of women among hospitalized heart failure patients is also high [7]. However, heart failure patients who are elderly and women are often not enrolled in clinical trials [22]. In addition, women with heart failure might respond differently than men [23]. Women are more likely to experience adverse effects from the use of ACE inhibitors, such as cough, taste disturbance, skin rash, gastrointestinal upset and a greater rise in creatinine [24, 25]. Among patients with myocardial infarction and left ventricular systolic dysfunction, female patients were less likely to experiences survival benefits from the use of an ACE inhibitors [26]. A subgroup analysis of data from the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) suggests a preferential survival benefit in men but not in women [27] Rathore et al. demonstrated that in women with heart failure and an ejection fraction of 45% or less, use of digoxin was associated with increased all-cause mortality (adjusted hazard ratio, 1.23; 95% confidence interval, 1.02 - 1.47) [14].
4.1 Mortality in women with heart failure
Our analysis confirms that women share many of the independent predictors of all-cause mortality as men, namely, increased age, longer duration of heart failure, higher NYHA classes, presence of diabetes mellitus, lower diastolic blood pressure, higher serum creatinine, presence of pulmonary congestion by chest x-ray, and lower ejection fraction [28, 29]. Martinez-Selles reported that ejection fraction was a predictor of mortality in men with heart failure, but not in women [30]. Other investigators have reported that women with heart failure and an abnormal LVEF have a higher mortality than women with a normal LVEF [2, 4, 5, 31, 32]. In our study, use of ACE inhibitors was associated with a non-significant 17% reduction in the risk of all-cause death. This is very likely due to the fact that the vast majority of patients in the DIG trial were taking ACE inhibitors, and only about 7% of the participants were not receiving ACE inhibitors. However, the non-significant effect of ACE inhibitors in women noted in our study is similar to that reported by a meta-analysis of randomized trials of ACE inhibitors [33]. In that study, there were 2,506 deaths in 10,367 men with systolic heart failure, and use of ACE inhibitors was associated with a significant 21% reduction in the odds for death (adjusted odds ratio, 0·79; 95% CI, 0·72–0·87). However, in 2,396 women, there were 671 deaths, and use of ACE inhibitors was associated with a non-significant 15% reduction in death (adjusted odd ratio, 0·85, 95% CI, 0·71–1·02) [33]. This underlies the importance of including more women in future clinical trials involving heart failure.
4.2 Hospitalization in women with heart failure
To our knowledge, no other study has documented independent predictors of hospitalization in women with prevalent heart failure. We found significant predictors of increased risk for hospitalization due to worsening heart failure in this cohort of ambulatory women were (age is p>0.05), longer duration of heart failure, higher NYHA classes, absence of myocardial infarction, presence of diabetes, higher heart rate, lower diastolic blood pressure, glomerular filtration rate, and left ventricular ejection fraction and presence of pulmonary congestion by X-ray. These same factors plus the presence of angina pectoris were also predictors of hospitalization due to all causes.
4.3 Diabetes, chronic kidney disease, and heart failure outcomes
Diabetes appears to be an important factor that not only increases the risk of death, but also of hospitalization, among ambulatory women with chronic heart failure. Several prior studies have reported an adverse effect of diabetes on survival in heart failure. Aronow et al. demonstrated the adverse effect of diabetes in heart failure patients with prior myocardial infarction [31, 32]. The deleterious effects of diabetes on outcomes in heart failure patients have been reported to be particular worse among those with ischemic cardiomyopathy [34, 35]. Among hospitalized heart failure patients, the effect of diabetes on mortality has been reported to be worse among women [36]. The strong association of diabetes with mortality and hospitalization found in the present analysis highlights the need for aggressive management of women with heart failure and diabetes.
Rising serum creatinine has been cited as a reason for underutilization of ACE inhibitors in heart failure patients [37]. The risk of increasing serum creatinine is higher for heart failure patients with diabetes [38]. However, the survival benefit of ACE inhibitors in heart failure patients and advanced kidney disease has been reported.[39] All women with heart failure and diabetes should be treated with ACE inhibitor [40].
4.3 Strengths and weaknesses
To our knowledge, this is the first analysis to examine predictors of outcomes in ambulatory women with chronic heart failure. Women in this study were recruited from over 300 centers in the US and Canada. Thus the results of this study are generalizable to a sizeable proportion of women with heart failure. Whereas nearly all large clinical trials in heart failure have included only individuals with reduced ejection fraction, almost half of the women with heart failure have preserved systolic function. Our study included women with heart failure across the spectrum of ejection fractions. Limitations of this study include lack of data on use of beta blockers, and all women were in sinus rhythm due to selection criteria for the DIG trial. Atrial fibrillation is common in heart failure and associated with poor outcomes [31, 41]. The benefits of beta blockers are now well established [42, 43].
4.4 Conclusions
In conclusion, we demonstrated that diabetes, NYHA class III-IV, pulmonary congestion by X-ray, decreasing glomerular filtration rate and reduced ejection fraction were predictors of increased all-cause mortality and heart failure related hospitalization among ambulatory women with chronic heart failure. Women with heart failure and diabetes have one of the highest risks for both outcomes, and special attention should be paid to the care these patients. Use of ACE inhibitors should be maximized in these patients.
Acknowledgments
“The Digitalis Investigation Group (DIG) study was conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the Digitalis Investigation Group (DIG) Investigators. This manuscript has been reviewed by NHLBI for scientific content and consistency of data interpretation with previous The Digitalis Investigation Group (DIG) publications and significant comments have been incorporated prior to submission for publication.”
Funding/Support: Dr. Ahmed is supported by a National Institutes of Health Mentored Patient-Oriented Research Career Development Award 1-K23-AG19211-01
References
- 1.Ahmed A, Roseman JM, Duxbury AS, Allman RM, DeLong JF. Correlates and outcomes of preserved left ventricular systolic function among older adults hospitalized with heart failure. Am Heart J. 2002;144(2):365–72. doi: 10.1067/mhj.2002.124058. [DOI] [PubMed] [Google Scholar]
- 2.Gottdiener JS, McClelland RL, Marshall R, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study. Ann Intern Med. 2002;137(8):631–9. doi: 10.7326/0003-4819-137-8-200210150-00006. [DOI] [PubMed] [Google Scholar]
- 3.Aronow WS, Ahn C, Kronzon I. Comparison of incidences of congestive heart failure in older African-Americans, Hispanics, and whites. Am J Cardiol. 1999;84(5):611–2. A9. doi: 10.1016/s0002-9149(99)00392-6. [DOI] [PubMed] [Google Scholar]
- 4.Pernenkil R, Vinson JM, Shah AS, Beckham V, Wittenberg C, Rich MW. Course and prognosis in patients > or = 70 years of age with congestive heart failure and normal versus abnormal left ventricular ejection fraction. Am J Cardiol. 1997;79(2):216–9. doi: 10.1016/s0002-9149(96)00719-9. [DOI] [PubMed] [Google Scholar]
- 5.Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol. 1999;33(7):1948–55. doi: 10.1016/s0735-1097(99)00118-7. [DOI] [PubMed] [Google Scholar]
- 6.Gustafsson F, Torp-Pedersen C, Burchardt H, et al. Female sex is associated with a better long-term survival in patients hospitalized with congestive heart failure. Eur Heart J. 2004;25(2):129–35. doi: 10.1016/j.ehj.2003.10.003. [DOI] [PubMed] [Google Scholar]
- 7.Ahmed A, Maisiak R, Allman RM, DeLong JF, Farmer R. Heart failure mortality among older Medicare beneficiaries: association with left ventricular function evaluation and angiotensin-converting enzyme inhibitor use. South Med J. 2003;96(2):124–9. doi: 10.1097/01.SMJ.0000051271.11872.50. [DOI] [PubMed] [Google Scholar]
- 8.Simon T, Mary-Krause M, Funck-Brentano C, Jaillon P. Sex differences in the prognosis of congestive heart failure: results from the Cardiac Insufficiency Bisoprolol Study (CIBIS II) Circulation. 2001;103(3):375–80. doi: 10.1161/01.cir.103.3.375. [DOI] [PubMed] [Google Scholar]
- 9.Adams KF, Jr, Dunlap SH, Sueta CA, et al. Relation between gender, etiology and survival in patients with symptomatic heart failure. J Am Coll Cardiol. 1996;28(7):1781–8. doi: 10.1016/S0735-1097(96)00380-4. [DOI] [PubMed] [Google Scholar]
- 10.Kimmelstiel C, Goldberg RJ. Congestive heart failure in women: focus on heart failure due to coronary artery disease and diabetes. Cardiology. 1990;77 Suppl 2:71–9. doi: 10.1159/000174655. [DOI] [PubMed] [Google Scholar]
- 11.Pijna IL, Buchter C. Heart failure in women. Cardiol Rev. 2003;11(6):337–44. doi: 10.1097/01.crd.0000087213.92777.a5. [DOI] [PubMed] [Google Scholar]
- 12.Koelling TM, Chen RS, Lubwama RN, L’Italien GJ, Eagle KA. The expanding national burden of heart failure in the United States: the influence of heart failure in women. Am Heart J. 2004;147(1):74–8. doi: 10.1016/j.ahj.2003.07.021. [DOI] [PubMed] [Google Scholar]
- 13.Klapholz M, Maurer M, Lowe AM, et al. Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: results of the New York Heart Failure Registry. J Am Coll Cardiol. 2004;43(8):1432–8. doi: 10.1016/j.jacc.2003.11.040. [DOI] [PubMed] [Google Scholar]
- 14.Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med. 2002;347(18):1403–11. doi: 10.1056/NEJMoa021266. [DOI] [PubMed] [Google Scholar]
- 15.Rationale, design, implementation, and baseline characteristics of patients in the DIG trial: a large, simple, long-term trial to evaluate the effect of digitalis on mortality in heart failure. Control Clin Trials. 1996;17(1):77–97. doi: 10.1016/0197-2456(95)00065-8. [DOI] [PubMed] [Google Scholar]
- 16.The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med. 1997;336(8):525–33. doi: 10.1056/NEJM199702203360801. [DOI] [PubMed] [Google Scholar]
- 17.Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461–70. doi: 10.7326/0003-4819-130-6-199903160-00002. [DOI] [PubMed] [Google Scholar]
- 18.SPSS for Windows, Rel. 12.0.2. program. SPSS Inc; 2004. [Google Scholar]
- 19.Gottdiener JS, Arnold AM, Aurigemma GP, et al. Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. J Am Coll Cardiol. 2000;35(6):1628–37. doi: 10.1016/s0735-1097(00)00582-9. [DOI] [PubMed] [Google Scholar]
- 20.Rodeheffer RJ, Jacobsen SJ, Gersh BJ, et al. The incidence and prevalence of congestive heart failure in Rochester, Minnesota. Mayo Clin Proc. 1993;68(12):1143–50. doi: 10.1016/s0025-6196(12)60063-9. [DOI] [PubMed] [Google Scholar]
- 21.Kannel WB, Belanger AJ. Epidemiology of heart failure. Am Heart J. 1991;121(3 Pt 1):951–7. doi: 10.1016/0002-8703(91)90225-7. [DOI] [PubMed] [Google Scholar]
- 22.Lindenfeld J, Krause-Steinrauf H, Salerno J. Where are all the women with heart failure? J Am Coll Cardiol. 1997;30(6):1417–9. doi: 10.1016/s0735-1097(97)00343-4. [DOI] [PubMed] [Google Scholar]
- 23.De Feo S, Opasich C. Comparison of the outcome in men and women with chronic heart failure. Ital Heart J. 2003;4(8):511–3. [PubMed] [Google Scholar]
- 24.Kostis JB, Shelton BJ, Yusuf S, et al. Tolerability of enalapril initiation by patients with left ventricular dysfunction: results of the medication challenge phase of the Studies of Left Ventricular Dysfunction. Am Heart J. 1994;128(2):358–64. doi: 10.1016/0002-8703(94)90490-1. [DOI] [PubMed] [Google Scholar]
- 25.Kostis JB, Shelton B, Gosselin G, et al. Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). SOLVD Investigators. Am Heart J. 1996;131(2):350–5. doi: 10.1016/s0002-8703(96)90365-8. [DOI] [PubMed] [Google Scholar]
- 26.Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med. 1995;333(25):1670–6. doi: 10.1056/NEJM199512213332503. [DOI] [PubMed] [Google Scholar]
- 27.Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet. 1999;353(9169):2001–7. [PubMed] [Google Scholar]
- 28.Kerzner R, Gage BF, Freedland KE, Rich MW. Predictors of mortality in younger and older patients with heart failure and preserved or reduced left ventricular ejection fraction. Am Heart J. 2003;146(2):286–90. doi: 10.1016/S0002-8703(03)00151-0. [DOI] [PubMed] [Google Scholar]
- 29.Schocken DD, Arrieta MI, Leaverton PE, Ross EA. Prevalence and mortality rate of congestive heart failure in the United States. J Am Coll Cardiol. 1992;20(2):301–6. doi: 10.1016/0735-1097(92)90094-4. [DOI] [PubMed] [Google Scholar]
- 30.Martinez-Selles M, Robles JA, Prieto L, et al. Systolic dysfunction is a predictor of long term mortality in men but not in women with heart failure. Eur Heart J. 2003;24(22):2046–2053. doi: 10.1016/j.ehj.2003.07.007. [DOI] [PubMed] [Google Scholar]
- 31.Aronow WS, Ahn C, Kronzon I. Prognosis of congestive heart failure after prior myocardial infarction in older persons with atrial fibrillation versus sinus rhythm. Am J Cardiol. 2001;87(2):224–5. A8–9. doi: 10.1016/s0002-9149(00)01324-2. [DOI] [PubMed] [Google Scholar]
- 32.Aronow WS, Ahn C, Kronzon I. Prognosis of congestive heart failure after prior myocardial infarction in older men and women with abnormal versus normal left ventricular ejection fraction. Am J Cardiol. 2000;85(11):1382–4. doi: 10.1016/s0002-9149(00)00777-3. [DOI] [PubMed] [Google Scholar]
- 33.Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. Lancet. 2000;355(9215):1575–81. doi: 10.1016/s0140-6736(00)02212-1. [DOI] [PubMed] [Google Scholar]
- 34.Domanski M, Krause-Steinrauf H, Deedwania P, et al. The effect of diabetes on outcomes of patients with advanced heart failure in the BEST trial. J Am Coll Cardiol. 2003;42(5):914–22. doi: 10.1016/s0735-1097(03)00856-8. [DOI] [PubMed] [Google Scholar]
- 35.De Groote P, Lamblin N, Mouquet F, et al. Impact of diabetes mellitus on long-term survival in patients with congestive heart failure. Eur Heart J. 2004;25(8):656–62. doi: 10.1016/j.ehj.2004.01.010. [DOI] [PubMed] [Google Scholar]
- 36.Gustafsson I, Brendorp B, Seibaek M, et al. Influence of diabetes and diabetes-gender interaction on the risk of death in patients hospitalized with congestive heart failure. J Am Coll Cardiol. 2004;43(5):771–7. doi: 10.1016/j.jacc.2003.11.024. [DOI] [PubMed] [Google Scholar]
- 37.Bart BA, Gattis WA, Diem SJ, O’Connor CM. Reasons for underuse of angiotensin-converting enzyme inhibitors in patients with heart failure and left ventricular dysfunction. American Journal of Cardiology. 1997;79(8):1118–20. doi: 10.1016/s0002-9149(97)00060-x. [DOI] [PubMed] [Google Scholar]
- 38.Knight EL, Glynn RJ, McIntyre KM, Mogun H, Avorn J. Predictors of decreased renal function in patients with heart failure during angiotensin-converting enzyme inhibitor therapy: results from the studies of left ventricular dysfunction (SOLVD) Am Heart J. 1999;138(5 Pt 1):849–55. doi: 10.1016/s0002-8703(99)70009-8. [DOI] [PubMed] [Google Scholar]
- 39.Ahmed A, Kiefe CI, Allman RM, Sims RV, DeLong JF. Survival benefits of angiotensin-converting enzyme inhibitors in older heart failure patients with perceived contraindications. J Am Geriatr Soc. 2002;50(10):1659–66. doi: 10.1046/j.1532-5415.2002.50457.x. [DOI] [PubMed] [Google Scholar]
- 40.Ryden L, Armstrong PW, Cleland JG, et al. Efficacy and safety of high-dose lisinopril in chronic heart failure patients at high cardiovascular risk, including those with diabetes mellitus. Results from the ATLAS trial. Eur Heart J. 2000;21(23):1967–78. doi: 10.1053/euhj.2000.2311. [DOI] [PubMed] [Google Scholar]
- 41.Ahmed A, Thornton P, Perry GJ, Allman RM, DeLong JF. Impact of atrial fibrillation on mortality and readmission in older adults hospitalized with heart failure. Eur J Heart Fail. 2004;6(4):421–426. doi: 10.1016/j.ejheart.2003.11.011. [DOI] [PubMed] [Google Scholar]
- 42.Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure) J Am Coll Cardiol. 2001;38(7):2101–13. doi: 10.1016/s0735-1097(01)01683-7. [DOI] [PubMed] [Google Scholar]
- 43.Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J. 2001;22(17):1527–60. doi: 10.1053/euhj.2001.2783. [DOI] [PubMed] [Google Scholar]