STATE-OF-THE-ART PAPER
Heart Failure in WomenA Need for Prospective Data
Eileen M. Hsich, MD*, ,* and
Ileana L. Piña, MD
* Department of Cardiovascular Medicine at the Cleveland Clinic, Cleveland, Ohio
Case Western Reserve University/Louis Stokes VA Medical Center, Cleveland, Ohio
Manuscript received September 10, 2008;
revised manuscript received February 5, 2009,
accepted February 9, 2009.
* Reprint requests and correspondence: Dr. Eileen M. Hsich, Kaufman Center for Heart Failure, Department of Cardiovascular Medicine, Cleveland Clinic, F-25, 9500 Euclid Avenue, Cleveland, Ohio 44195 (Email: Hsiche{at}ccf.org).
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Abstract
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Heart failure affects 5 million Americans, and nearly 50% of these are women. Sex differences have been noted regarding the underlying etiology, pathophysiology, and prognosis. Women are less likely to have coronary artery disease and more likely than men to have hypertension and valvular disease as the underlying etiology. They often present at an older age with better systolic function than men. For both sexes, there is significant morbidity, but age-adjusted data reveal that women have a better survival. Despite these known sex differences, medical management recommendations are the same for women and men, because prospective sex-specific clinical trials have not been performed. However, our review raises some concerns that women might respond differently to therapy.
Key Words: heart failure • sex • women
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Abbreviations and Acronyms
| | ACEI = angiotensin-converting enzyme inhibitor | | ARB = angiotensin receptor blocker | | CAD = coronary artery disease | | CI = confidence interval | | CVD = cardiovascular disease | | HF = heart failure | | HR = hazard ratio | | ICD = implantable cardioverter-defibrillator | | LV = left ventricular | | LVEF = left ventricular ejection fraction | | NIH = National Institutes of Health | | NYHA = New York Heart Association | | PPCM = peripartum cardiomyopathy | | RR = relative risk |
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More women die every year of cardiovascular disease (CVD) than of breast or uterine cancer. Although nearly 50% of the female CVD mortality is due to coronary heart disease, heart failure (HF) contributes 35% of the total female CVD mortality (1). Despite this fact, HF in women remains a poorly recognized and poorly understood syndrome and has not received the same public awareness as coronary heart disease. The objective of this work is to review sex differences in epidemiology, etiology, diagnosis, and prognostic testing and discuss sex-specific results from the landmark HF trials that have shaped our current medical practice. In addition, to guide practitioners when caring for women with HF, this review will offer practical suggestions. For sex differences in HF pathophysiology, we refer readers to the excellent review by Konhilas and Leinwand (2).
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Epidemiology/Prognosis/Etiology
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Heart failure affects 5.3 million Americans, and nearly 50% of these are women (1). The prevalence of HF increases with age for both sexes, with more women than men having HF after 79 years of age (1). Women with acute decompensated HF tend to have HF with preserved left ventricular (LV) function almost twice as often as men (3,4), and those with impaired LV systolic function tend to present with a higher left ventricular ejection fraction (LVEF) when compared with men (3). Additionally, comorbidities are common. Women with HF tend to have more hypertension compared with men, who have more smoking and coronary artery disease (CAD) (5). Thyroid disease is more frequent in women with acute decompensated HF, whereas chronic obstructive lung disease, peripheral vascular disease, and renal insufficiency are more common in men (3,4).
Age-adjusted HF incidence is higher in men than in women, yet the prevalence is similar, because men with HF have shorter survival than women (6,7). The incidence of HF from 1979 to 2000 rose 8% (95% confidence interval [CI]: –5% to 23%) in women and 3% (95% CI: –11% to 20%) in men according to the Olmsted County data (6), which validated 4,537 cases of new onset HF. Similarly, the Framingham investigators also reported an increase in the incidence of HF for both women and men between 1980 and 1999 (7). During those time periods, age-adjusted, 5-year mortality improved for both sexes (6,7).
There is significant morbidity associated with HF, and women have been shown to have a lower quality of life than men, with more functional capacity impairment (8), more HF hospital stays (1,3,8), and depression (9). Nonetheless, survival is better for women (6,7). The cause for sex differences in mortality remains unknown, but 2 leading hypotheses are differences in systolic function and in etiology. Women are more likely than men to have HF with preserved LV systolic function, which was believed to have a better prognosis than impaired LV function. However, 2 recent observational studies showed a similar mortality rate for HF patients with preserved or impaired systolic function (10,11). Women also have less ischemic cardiomyopathy, and survival might be related to sex differences in etiology (12). Although the CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) study noted that sex differences in survival were not entirely explained by LV systolic function or by etiology, there was a worse prognosis for both women and men with ischemic cardiomyopathy (Fig. 1) (5).
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Figure 1 Kaplan-Meier Curves for All-Cause Mortality in the CHARM Study
Kaplan-Meier curves for all-cause mortality in the CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) study for women and men with heart failure on the basis of the presence or absence of an ischemic cardiomyopathy. Adapted from O'Meara et al. (5).
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Tests used for survival prediction might require sex-specific interpretation. For example, brain natriuretic peptide >500 pg/ml might be a stronger predictor of death in women with HF than in men (13). Cardiopulmonary exercise testing, often used to determine optimal timing for listing for heart transplantation, seems to be an excellent predictor of death in both women and men (14), but for any given peak oxygen consumption women have a better survival (14,15). However, women with an ischemic cardiomyopathy have a worse prognosis compared with those women with a nonischemic cardiomyopathy for any given peak oxygen consumption (Fig. 2) (14).
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Figure 2 Adjusted Predicted Mortality
Adjusted predicted mortality in women with heart failure and impaired systolic function on the basis of peak oxygen consumption (VO2) and the presence or absence of coronary artery disease (CAD). Adapted from Hsich et al. (14).
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Heart failure is associated with many risk factors with some sex differences. Women are more likely than men to have hypertension and valvular disease as the underlying etiology for HF and less likely to have CAD (3–5). Although CAD is less common, it is such a significant risk factor that women are more likely to develop HF with CAD than with hypertension. For example, in the NHANES (National Health and Nutrition Examination Survey) I survey—which included 8,098 women without HF—27% had hypertension and only 3% had CAD, but the relative risk (RR) of developing HF for women was significantly higher if they had CAD (RR: 8.16; 95% CI: 6.79 to 9.8; p < 0.001) than if they had hypertension (RR: 1.51; 95% CI: 1.29 to 1.77; p < 0.001) (16). Diabetes mellitus is common in both sexes (i.e., 44%) (3) and is one of the strongest additional risk factors for the development of HF in women with CAD (17). Other causes of HF include cardiac toxicity from chemotherapeutic agents used to treat breast malignancy and peripartum cardiomyopathy (PPCM).
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PPCM
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PPCM is the development of HF with impaired systolic function in the last month of pregnancy or within 5 months post-partum with no pre-existing cardiac disease or identifiable cause (18). The incidence varies on the basis of the population studied, with an estimated occurrence in 1 of 4,000 pregnancies in the U.S. (18). The etiology remains unknown, but potential causes include myocarditis, abnormal immune response to pregnancy, increased myocyte apoptosis, genetic predisposition, and proteolytic cleavage of prolactin during oxidative stress. Risk factors include advanced maternal age, African descent, high parity, twin pregnancy, usage of tocolytics, and poverty (19). Approximately one-half of PPCM patients recover normal systolic function within 6 months (20). Another 20% deteriorate and either die or require heart transplantation (21). The degree of LV systolic dysfunction at presentation might predict recovery. In 1 study involving 33 patients with PPCM, those who recovered LV systolic function had a higher LVEF at presentation (LVEF 35 ± 4% vs. 25 ± 4%, p = 0.001) (22). In another study involving 98 patients from Haiti with PPCM, a similar finding was noted, with recovery more likely in patients with less severe systolic dysfunction (LVEF 28%, 95% CI: 15% to 41% vs. LVEF 23%, 95% CI: 11% to 35%, p < 0.001) (23). There are limited data regarding the risk of subsequent pregnancies. One retrospective study noted that the average LVEF after subsequent pregnancy was reduced both in patients who had recovered systolic function before pregnancy (n = 28; LVEF 56 ± 7% reduced to 49 ± 10%, p = 0.002) and in those with persistent LV systolic dysfunction (n = 16; LVEF 36 ± 9% reduced to 32 ± 11%, p = 0.08). All 3 patients who died in this series had LV systolic dysfunction before the subsequent pregnancy (24). Preliminary data involving animal research and 12 PPCM patients suggest that bromocriptine, which inhibits prolactin secretion, might help prevent death and deterioration of LV function upon subsequent pregnancies by preventing the formation of a 16-kDA prolactin fragment. An imbalance of oxidative stress during pregnancy or in the peripartum period can cause prolactin to be cleaved by cathepsin D into a 16-kDA prolactin fragment, which can destroy the cardiac microvasculature and lead to LV cavity dilation and systolic dysfunction (25). The 16-kDA prolactin fragment induces endothelial apoptosis (26), inhibits vascular endothelial growth factor-induced proliferation of endothelial cells, and impairs nitric oxide-mediated vasorelaxation (27). Although this is potentially an exciting breakthrough in the pathophysiology of PPCM, the data are preliminary, and the usage of bromocriptine in the post-partum period to suppresses lactation has been associated with increased incidence of cardiovascular events, hypertension, and thrombus formation (19). Therefore, it is reasonable to await the results of larger studies with usage of bromocriptine and to counsel women who have a diagnosis of PPCM about subsequent pregnancies and the need to remove angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) therapy should a new pregnancy occur.
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Diagnosis
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The diagnosis of HF is a clinical diagnosis based on a constellation of symptoms and signs (28). According to the SOLVD (Studies Of Left Ventricular Dysfunction) database, women with impaired systolic LV function are more likely than men to have dependent edema, jugular venous distension, and an S3 gallop (29). In contrast, according to ADHERE (Acute Decompensated Heart Failure National Registry) (impaired and preserved systolic function), there were no clinically important differences in the frequency of HF symptoms/signs between women (n = 54,674) and men (n = 50,713) (3). This apparent difference in symptom observation might be related to the fact that the ADHERE registry was derived from patients hospitalized for acute decompensation compared with most clinical trials where patients present with chronic symptoms.
Diagnostic tests to assess LV function are frequently used to further classify HF patients into those with impaired or preserved LV systolic function and to assess for other structural heart disease. From both the Framingham and the Olmstead County databases, more women than men have HF with preserved LV function (30,31) as depicted in Figure 3. Coronary angiography might determine who has an ischemic cardiomyopathy. Brain natriuretic peptide, a biomarker, is being used more frequently to identify patients with symptoms of HF and to risk stratify. However, "normal" brain natriuretic peptide values are higher in women versus men (32). More studies are needed that will address sex differences in biomarker levels and strategies to intervene on outcomes. Sufficient women need to be enrolled so that analyses can be carried out by sex.
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Therapy
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Most clinical trials have not planned to prospectively analyze the female cohort or enroll a certain percentage of women. One exception is BEST (Beta-Blocker Evaluation of Survival Trial), which stratified patients by sex (12). Consequently, current guidelines for HF therapy (28,33) are not sex specific due to under-representation of women (Table 1) and lack of sex-specific, prospective, randomized clinical trials. The summaries that follow refer mostly to HF with impaired systolic function and should be interpreted with caution, because they have been derived from retrospective studies or post hoc analyses.
ACEI.
ACEIs are currently recommended for all patients with HF and impaired systolic function, because of the known morbidity and mortality benefits (28,34). Unfortunately, few women participated in these landmark HF clinical trials, and therefore the benefits in women remain unclear. A meta-analysis consisting of 30 ACEI studies involving a total of 1,587 women with HF demonstrated a trend toward improved survival in the group taking ACEIs compared with those not taking the drug (13.4% vs. 20.1%) and a favorable trend in the combined end point of survival and hospital stay in the group of women taking an ACEI (20.2% vs. 29.5%) (35). Another meta-analysis involving 2,373 women revealed similar trends and noted that women who were symptomatic benefited more than those who were asymptomatic (36). However, both meta-analyses had wide CIs that crossed 1.0, raising some uncertainty about the actual benefit (Table 2).
ARBs.
Angiotensin receptor blockers are used in ACEI-intolerant HF patients or in addition to an ACEI (28). Sex-specific data for ARBs are limited, but candesartan and valsartan seem beneficial in women. Pooled data from the CHARM-Alternative (ARB for patients intolerant of ACEI) and CHARM-Added trials (ARB added to an ACEI) that included 1,188 women, New York Heart Association (NYHA) functional class II to IV with LVEF  40%, showed that candesartan reduced the combined end point of cardiovascular death or HF hospital stay in women (37). In the Val-HeFT (Valsartan Heart Failure Trial), which included 1,003 women with NYHA functional class II to IV and LVEF <40%, valsartan when compared with placebo did not significantly reduce mortality in women but did reduce HF hospital stay (hazard ratio [HR]: 0.74, 95% CI: 0.55 to 0.98) and first morbid event (HR: 0.79, 95% CI: 0.63 to 0.99) (I. Anand, personal communication, April 22, 2008), which was defined as cardiac arrest, HF hospital stay, or administration of intravenous inotrope/vasodilator therapy (Table 2) (38).
Beta-blockers.
Three beta-blockers are proven in multicenter, prospective, randomized studies to reduce mortality and morbidity in HF patients with impaired systolic function: carvedilol, bisoprolol, and metoprolol succinate. Post hoc analyses suggest that these agents, when added to an ACEI, are beneficial in women with HF despite the relatively small number of female participants in each study.
Carvedilol is a nonselective beta-adrenergic antagonist with alpha-blocking and antioxidant properties. Carvedilol improved survival in the 256 women participating in the U.S. Carvedilol Heart Failure Study of HF patients with moderate symptoms and LVEF 35% (HR: 0.23, 95% CI: 0.07 to 0.69) (39), although this was not a mortality trial. In the COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival Study) study, carvedilol reduced the combined end point of death or hospital stay in the 469 women studied with LVEF <25% and severe HF symptoms. Most of this benefit was due to a reduction in hospital stays, because the mortality data had a wide CI and the HR crossed 1.0 (40).
Bisoprolol and metoprolol succinate are beta1-selective adrenergic antagonists. In the European CIBIS II (Cardiac Insufficiency Bisoprolol Study), bisoprolol improved survival in the 515 women studied who were NYHA functional class III or IV and had LVEF 35% (relative hazard: 0.37, 95% CI: 0.19 to 0.69) (41). In the MERIT-HF (Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure) trial, metoprolol succinate had no survival benefit for women (6.9% vs. 7.5%, p = NS) but did reduce HF hospital stay by 42% (p = 0.021) in the 898 women studied with LVEF <40% who were NYHA functional class II to IV. This effect was even more dramatic with a 72% reduction in HF hospital stays (0.54 vs. 0.15; p = 0.0004) in the subgroup of women (n = 183 patients) with LVEF <25% (42).
Aldosterone antagonists.
Aldosterone antagonists are one of the few medications deemed by subgroup post hoc analysis to have a total mortality benefit for women with systolic HF on the basis of both the RALES (Randomized Aldactone Evaluation Study) and EPHESUS (Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trials (43,44). The RALES trial included 446 women and studied the effects of spironolactone in ischemic and nonischemic cardiomyopathy patients with NYHA functional class III to IV and LVEF 35% (43). The EPHESUS trial included 1,918 women participants and studied the effects of eplerenone after an acute myocardial infarction in patients with LVEF 40% (44).
Hydralazine/isosorbide dinitrate.
The combination of hydralazine and isosorbide dinitrate has been commonly used in HF patients who cannot tolerate an ACEI or ARB. The original data supporting the use of this combination by demonstrating a survival benefit included only men (45,46). In fact there remain no published data for women using hydralazine and isosorbide dinitrate as a substitute for an ACEI or ARB. Added to ACEI/ARB and beta-blockers, this combination has been studied in the A-HeFT (African-American Heart Failure Trial), which included 420 women participants who were NYHA functional class III to IV. The trial was prematurely stopped because of the significant survival benefits that were noted for both women (HR: 0.33, 95% CI: 0.16 to 0.71, p = 0.003) and men (HR: 0.79, 95% CI: 0.46 to 1.35, p = 0.385) with no significant treatment interaction by sex. There were also fewer first hospital stays for HF in both women (HR: 0.62, 95% CI: 0.41 to 0.96, p = 0.03) and men (HR: 0.60, 95% CI: 0.42 to 0.89, p = 0.005) (47).
Digoxin.
Digoxin reduces HF hospital stay but has no beneficial effect on survival (48).
In women with impaired systolic function, there was an initial concern of increased mortality (adjusted HR: 1.23, 95% CI: 1.02 to 1.47) that was not observed in men (adjusted HR: 0.93, 95% CI: 0.85 to 1.02) on the basis of a post hoc subgroup analysis of the Digitalis Investigation Group trial (49). The increased mortality was presumed to be due to digoxin toxicity, because the risk of death increased at higher serum drug levels. Drug levels between 1.2 and 2.0 ng/ml were associated with increased mortality (HR: 1.33, 95% CI: 1.001 to 1.76, p = 0.049), and levels between 0.5 and 0.9 ng/ml were considered safe for both women and men (HR: 0.8) on the basis of a retrospective analysis (50).
Antiplatelet agents and anticoagulation.
In a retrospective analysis of the SOLVD trial, women with HF had an increased risk of thromboembolic events compared with men. Although women had more thromoboembolic events (mostly pulmonary embolic events) they were also less likely than men to be taking antiplatelet agents or anticoagulation therapy. In fact, the use of an antiplatelet agent in women significantly reduced the likelihood of this complication (51). Further information regarding this topic might be provided by the ongoing WARCEF (Warfarin Versus Aspirin in Reduced Ejection Fraction) trial.
Cardiac resynchronization therapy (CRT).
CRT is recommended for HF patients with LVEF 35%, NYHA functional class III to IV symptoms in spite of optimal medical therapy, and a wide QRS (QRS  120 ms), on the basis of large, prospective, randomized multicenter studies that demonstrated improvement in symptoms, functional capacity, and mortality (52,53). Although few studies have reported sex-specific data, it seems that CRT is beneficial for both women and men. In the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) study, which included 299 women, women with CRT had a greater reduction in the combined end point of total mortality or hospital stay for any cause compared with women given just medical therapy (52). A retrospective analysis of the CARE-HF (Cardiac Resynchronization–Heart Failure) data—a study that included 215 women—suggested that CRT was preferable to medical therapy alone in women for the combined end point of total mortality and hospital stay for major cardiovascular events (Table 2). All patients were functional NYHA functional class III or IV, had LVEF 35%, LV end-diastolic diameter 30 mm as indexed for height, and QRS >120 ms with evidence of dyssynchrony if QRS was 120 to 149 ms (53).
Implantable cardioverter-defibrillator (ICD).
The recommendations for an ICD to prevent sudden death are based on many multicenter studies, but few have provided sex-specific data (52,54). Unfortunately, the limited post hoc analyses available for women with an ICD do not clearly demonstrate a mortality benefit (52,54,55). In the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), which included 588 women in NYHA functional class II to III with LVEF 35% (ischemic and nonischemic cardiomyopathy), the benefits of an ICD were not clear, although the trial was not powered to detect sex differences (women HR: 0.96, 95% CI: 0.58 to 1.61). In the MADIT (Multicenter Automatic Defibrillator Implantation Trial) II, which included 119 women with an ischemic cardiomyopathy LVEF 30%, there was a nonsignificant trend toward lower mortality in women with an ICD (adjusted HR: 0.57, p = 0.132), suggesting that this subgroup (ischemic cardiomyopathy) might benefit. However, this analysis was limited by too few women participants (55).
Ventricular assist device (VAD).
VADs are used in critically ill HF patients as a "bridge" to heart transplantation or as "destination therapy" for those who have failed medical therapy and are ineligible for heart transplantation. There is no sex difference in the surgical technique for implanting these devices. However, small women have limited options, because devices like implantable left VADs require a minimum body surface to fit properly.
The VAD outcome data comparing women and men remain limited (56,57). One study noted that women were more likely than men to require a right VAD after implantation of a left VAD, but there were few women participants and pre-VAD implantation data were not analyzed (56). In another study in which women had a worse prognosis, women were clinically more unstable than men before VAD implantation. Survival after VAD correlated best with the degree of medical severity before VAD implantation and not sex (57). The recent Food and Drug Administration approval of the HeartMate II (Thoratec Corporation, Pleasanton, California) a small continuous flow device, will allow the implantation of more VADs in women and enable data analysis in a more consistent prospective manner, because it will be added to the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) National Heart, Lung, and Blood Institute patient registry for VADs.
Heart transplantation.
In the U.S. for 2007, women donated 28% of the available hearts and received 26% of the hearts transplanted. The overall survival after transplantation on the basis of UNOS (United Network of Organ Sharing) data from 1997 to 2004 was slightly worse for women (i.e., survival rate female vs. male: 1 year 86% vs. 88%, 3 years 76% vs. 79%, 5 years 68% vs. 72%) (58). The most recent data (2007) from the International Society for Heart and Lung Transplantation (59) showed that the sex of the donor or recipient did not significantly affect 1-year mortality but that the RR of 5-, 10-, and 15-year mortality was slightly increased for male recipients who received female hearts (5-year RR: 1.2, 95% CI: 1.05 to 1.37, p = 0.0093; 10-year RR: 1.08, 95% CI: 1.01 to 1.17, p = 0.0309; 15-year RR: 1.13, 95% CI: 1.01 to 1.25, p = 0.0334). With respect to coronary allograft vasculopathy, the RR within 5 years was highest for recipients who received male donor hearts and lowest for female recipients who received female donor hearts (59).
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Conclusions
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Approximately 2.7 million women have HF. Heart failure affects women at an older age with better LV systolic function, compared with men. Women are more likely to have hypertension and valvular disease as the etiology and less likely to have CAD. However, CAD is such an important risk factor that a woman with CAD is more likely to develop HF than a woman with hypertension. Survival for women with HF is better than for men, and the reason remains unclear but might in part be related to sex differences in etiology, with a worse survival in both women and men with ischemic cardiomyopathy.
Since the landmark HF in women review article by Petrie et al. (60) in 1999, which was striking mainly because of the lack of sex-specific data, we have learned more regarding epidemiology, prognostic testing, and the rare disease PPCM. We continue to know little sex-specific information regarding therapy. At least 9 multicenter HF studies have been published since Petrie's article (i.e., RALES [43], EPHESUS [44], A-HeFT [47], CHARM [37], ELITE II [Losartan Heart Failure Survival Study] [61], Val-HeFT [38], COPERNICUS [40], COMPANION [52], and CARE-HF [53]) and on average included 28% women. This is an improvement in enrollment compared with the 19% reported by Petrie et al. but still an under-representation for a disease that has approximately 40% women with impaired systolic function and 60% women with preserved LV function (3). Our current HF guidelines are not sex specific because of insufficient data, but our review of the published reports raises concern that sex differences might exist regarding the degree of benefit of any given therapy. For instance, retrospective analysis revealed a morbidity and/or mortality benefit for HF women treated with beta-blockers, aldosterone antagonists, or CRT but did not show the same benefit with ACEI or ICD, despite all studies having a paucity of female participants.
What do we need to do to change the future? Since 1986 the National Institutes of Health (NIH) has requested that women be included in clinical trials, and in 1993 an NIH Revitalization Act was passed that stipulated that a sufficient number of women be included in NIH-sponsored trials to report meaningful sex-specific results. Despite the NIH attempts, there continues to be a low rate of sex-specific reporting in cardiovascular trials (62). Although journal editors could require sex-specific results, it does not change the fact that most clinical HF trials were not designed to even determine sex differences. Changes need to be made, but who should accept this responsibility and how to enforce it remains controversial.
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Footnotes
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This work was supported by American Heart Association Scientist Development Grant 0730307N.
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References
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1. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation 2008;117:e25-e146.[Free Full Text]2. Konhilas JP, Leinwand LA. The effects of biological sex and diet on the development of heart failure Circulation 2007;116:2747-2759.[Free Full Text] 3. Galvao M, Kalman J, DeMarco T, et al. Gender differences in in-hospital management and outcomes in patients with decompensated heart failure: analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) J Card Fail 2006;12:100-107.[CrossRef][Web of Science][Medline] 4. Nieminen MS, Harjola VP, Hochadel M, et al. Gender related differences in patients presenting with acute heart failure. Results from EuroHeart Failure Survey II. Eur J Heart Fail 2008;10:140-148.[Abstract/Free Full Text] 5. O'Meara E, Clayton T, McEntegart MB, et al. Sex differences in clinical characteristics and prognosis in a broad spectrum of patients with heart failure: results of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program Circulation 2007;115:3111-3120.[Abstract/Free Full Text] 6. Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population JAMA 2004;292:344-350.[Abstract/Free Full Text] 7. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure N Engl J Med 2002;347:1397-1402.[CrossRef][Web of Science][Medline] 8. Deswal A, Bozkurt B. Comparison of morbidity in women versus men with heart failure and preserved ejection fraction Am J Cardiol 2006;97:1228-1231.[CrossRef][Web of Science][Medline] 9. Gottlieb SS, Khatta M, Friedmann E, et al. The influence of age, gender, and race on the prevalence of depression in heart failure patients J Am Coll Cardiol 2004;43:1542-1549.[Abstract/Free Full Text] 10. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction N Engl J Med 2006;355:251-259.[CrossRef][Medline] 11. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study N Engl J Med 2006;355:260-269.[CrossRef][Medline] 12. Ghali JK, Krause-Steinrauf HJ, Adams KF, et al. Gender differences in advanced heart failure: insights from the BEST study J Am Coll Cardiol 2003;42:2128-2134.[Abstract/Free Full Text] 13. Christ M, Laule-Kilian K, Hochholzer W, et al. Gender-specific risk stratification with B-type natriuretic peptide levels in patients with acute dyspnea: insights from the B-type natriuretic peptide for acute shortness of breath evaluation study J Am Coll Cardiol 2006;48:1808-1812.[Abstract/Free Full Text] 14. Hsich E, Chadalavada S, Krishnaswamy G, et al. Long-term prognostic value of peak oxygen consumption in women versus men with heart failure and severely impaired left ventricular systolic function Am J Cardiol 2007;100:291-295.[CrossRef][Web of Science][Medline] 15. Elmariah S, Goldberg LR, Allen MT, Kao A. Effects of gender on peak oxygen consumption and the timing of cardiac transplantation J Am Coll Cardiol 2006;47:2237-2242.[Abstract/Free Full Text] 16. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study Arch Intern Med 2001;161:996-1002.[Abstract/Free Full Text] 17. Bibbins-Domingo K, Lin F, Vittinghoff E, et al. Predictors of heart failure among women with coronary disease Circulation 2004;110:1424-1430.[Abstract/Free Full Text] 18. Pearson GD, Veille JC, Rahimtoola S, et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review JAMA 2000;283:1183-1188.[Abstract/Free Full Text] 19. Ntusi NB, Mayosi BM. Aetiology and risk factors of peripartum cardiomyopathy: a systematic review Int J Cardiol 2009;131:168-179.[CrossRef][Web of Science][Medline] 20. Hu CL, Li YB, Zou YG, et al. Troponin T measurement can predict persistent left ventricular dysfunction in peripartum cardiomyopathy Heart 2007;93:488-490.[Abstract/Free Full Text] 21. Abboud J, Murad Y, Chen-Scarabelli C, Saravolatz L, Scarabelli TM. Peripartum cardiomyopathy: a comprehensive review Int J Cardiol 2007;118:295-303.[CrossRef][Web of Science][Medline] 22. Duran N, Gunes H, Duran I, Biteker M, Ozkan M. Predictors of prognosis in patients with peripartum cardiomyopathy Int J Gynaecol Obstet 2008;101:137-140.[CrossRef][Medline] 23. Fett JD, Christie LG, Carraway RD, Murphy JG. Five-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution Mayo Clin Proc 2005;80:1602-1606.[Abstract/Free Full Text] 24. Elkayam U, Tummala PP, Rao K, et al. Maternal and fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy N Engl J Med 2001;344:1567-1571.[CrossRef][Web of Science][Medline] 25. Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy Cell 2007;128:589-600.[CrossRef][Web of Science][Medline] 26. Tabruyn SP, Sorlet CM, Rentier-Delrue F, et al. The antiangiogenic factor 16K human prolactin induces caspase-dependent apoptosis by a mechanism that requires activation of nuclear factor-kappaB Mol Endocrinol 2003;17:1815-1823.[Abstract/Free Full Text] 27. Gonzalez C, Corbacho AM, Eiserich JP, et al. 16K-prolactin inhibits activation of endothelial nitric oxide synthase, intracellular calcium mobilization, and endothelium-dependent vasorelaxation Endocrinology 2004;145:5714-5722.[CrossRef][Web of Science][Medline] 28. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2009;53:e1-e90.[Free Full Text] 29. Johnstone D, Limacher M, Rousseau M, et al. Clinical characteristics of patients in studies of left ventricular dysfunction (SOLVD) Am J Cardiol 1992;70:894-900.[CrossRef][Web of Science][Medline] 30. Redfield MM, Jacobsen SJ, Burnett Jr. JC, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic JAMA 2003;289:194-202.[Abstract/Free Full Text] 31. 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;33:1948-1955.[Abstract/Free Full Text] 32. Wang TJ, Larson MG, Levy D, et al. Impact of age and sex on plasma natriuretic peptide levels in healthy adults Am J Cardiol 2002;90:254-258.[CrossRef][Web of Science][Medline] 33. Heart Failure Society of America Executive summary: HFSA 2006 comprehensive heart failure practice guideline J Card Fail 2006;12:10-38.[CrossRef][Web of Science][Medline] 34. The CONSENSUS Trial Study Group Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435.[Web of Science][Medline] 35. Garg R, Yusuf S, Collaborative Group on ACE Inhibitor Trials Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure JAMA 1995;273:1450-1456.[Abstract/Free Full Text] 36. Shekelle PG, Rich MW, Morton SC, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials J Am Coll Cardiol 2003;41:1529-1538.[Abstract/Free Full Text] 37. Young JB, Dunlap ME, Pfeffer MA, et al. Mortality and morbidity reduction with Candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials Circulation 2004;110:2618-2626.[Abstract/Free Full Text] 38. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure N Engl J Med 2001;345:1667-1675.[CrossRef][Web of Science][Medline] 39. Packer M, Bristow MR, Cohn JN, et al. U.S. Carvedilol Heart Failure Study Group The effect of carvedilol on morbidity and mortality in patients with chronic heart failure N Engl J Med 1996;334:1349-1355.[CrossRef][Web of Science][Medline] 40. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure N Engl J Med 2001;344:1651-1658.[CrossRef][Web of Science][Medline] 41. 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;103:375-380.[Abstract/Free Full Text] 42. Ghali JK, Pina IL, Gottlieb SS, Deedwania PC, Wikstrand JC. Metoprolol CR/XL in female patients with heart failure: analysis of the experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF) Circulation 2002;105:1585-1591.[Abstract/Free Full Text] 43. Pitt B, Zannad F, Remme WJ, et al. Randomized Aldactone Evaluation Study Investigators The effect of spironolactone on morbidity and mortality in patients with severe heart failure N Engl J Med 1999;341:709-717.[CrossRef][Web of Science][Medline] 44. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction N Engl J Med 2003;348:1309-1321.[CrossRef][Web of Science][Medline] 45. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-1552.[Web of Science][Medline] 46. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure N Engl J Med 1991;325:303-310.[Web of Science][Medline] 47. Taylor AL, Lindenfeld J, Ziesche S, et al. Outcomes by gender in the African-American Heart Failure Trial J Am Coll Cardiol 2006;48:2263-2267.[Abstract/Free Full Text] 48. The Digitalis Investigation Group The effect of digoxin on mortalitymorbidity in patients with heart failure N Engl J Med 1997;336:525-533.[CrossRef][Web of Science][Medline] 49. 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;347:1403-1411.[CrossRef][Web of Science][Medline] 50. Adams Jr. KF, Patterson JH, Gattis WA, et al. Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis J Am Coll Cardiol 2005;46:497-504.[Abstract/Free Full Text] 51. Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials J Am Coll Cardiol 1997;29:1074-1080.[Abstract] 52. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure N Engl J Med 2004;350:2140-2150.[CrossRef][Web of Science][Medline] 53. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure N Engl J Med 2005;352:1539-1549.[CrossRef][Web of Science][Medline] 54. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure N Engl J Med 2005;352:225-237.[CrossRef][Web of Science][Medline] 55. Zareba W, Moss AJ, Jackson Hall W, et al. Clinical course and implantable cardioverter defibrillator therapy in postinfarction women with severe left ventricular dysfunction J Cardiovasc Electrophysiol 2005;16:1265-1270.[Web of Science][Medline] 56. Ochiai Y, McCarthy PM, Smedira NG, et al. Predictors of severe right ventricular failure after implantable left ventricular assist device insertion: analysis of 245 patients Circulation 2002;106:I198-I202.[CrossRef][Web of Science][Medline] 57. Morgan JA, Weinberg AD, Hollingsworth KW, Flannery MR, Oz MC, Naka Y. Effect of gender on bridging to transplantation and posttransplantation survival in patients with left ventricular assist devices J Thorac Cardiovasc Surg 2004;127:1193-1195.[Free Full Text] 58. Organ Procurement and Transplantation Network http://optn.transplant.hrsa.gov/latestData/step2.asp 2004Accessed June 16, 2009. 59. International Society for Heart and Lung Transplantation http://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry 2004Accessed March 24, 2008. 60. Petrie MC, Dawson NF, Murdoch DR, Davie AP, McMurray JJ. Failure of women's hearts Circulation 1999;99:2334-2341.[Free Full Text] 61. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial—the Losartan Heart Failure Survival Study ELITE II Lancet 2000;355:1582-1587.[CrossRef][Web of Science][Medline] 62. Blauwet LA, Hayes SN, McManus D, Redberg RF, Walsh MN. Low rate of sex-specific result reporting in cardiovascular trials Mayo Clin Proc 2007;82:166-170.[Abstract/Free Full Text]
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