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Abstract

This article reviews literature pertinent to cardiovascular disparities in women, focusing primarily on heart failure (HF). It provides an in-depth look at causes, biological influences, self-management and lack of adherence to HF-treatment guidelines in women. Disparities in treatment of causative factors of HF, such as myocardial infarction and hypertension, contribute to women having poorer HF outcomes than men. This article discusses major contributing reasons for nonadherence to medication regimes for HF in women, including advanced age at time of diagnosis, likelihood of multiple comorbidities, lack of social support and low socioeconomic status. Limited inclusion of women in clinical trials and the scarcity of gender analyses for HF and other cardiovascular diseases continues to limit the applicability of research findings to women.

Keywords

cardiovascular disease gender differences heart failure treatment women

Cardiovascular disease (CVD) is the leading cause of death in women in the USA and kills more women than the next three leading causes of death combined [l]. Despite the fact that CVD kills more women than any other cause [l], women may receive less aggressive treatment for risk factors and are often not treated to recommended guidelines for a myriad of CVD diagnoses [2 –5]. Without proper control, risk factors predispose women and men to the development of heart failure (HF).

HF is a nebulous condition, often difficult to define, sometimes misdiagnosed and may be miscoded as other conditions. It is a debilitating and deadly chronic disease; approximately 50% of people diagnosed with HF die within 5 years [1,6], similar to a cancer prognosis [3]. Almost 6 million adults in the USA have HF, causing approximately 300,000 deaths per year [l]. Approximately 2% of women and 3% of men have HF [l] and it is most prevalent among black individuals; 3.8% of black females and 4.5% of black males have HF compared with 1.8% of white females and 2.7% of white males (age-adjusted percentage of adults ≥20 years of age) [l]. Overall, women comprise approximately 50% of the adults diagnosed with HF [1,5].

HF may be diagnosed in patients with and without preserved ejection fraction. Diagnosis is based primarily on symptomatology. The chronic nature of HF results in reduced activity tolerance and quality of life, frequent hospitalizations and premature death, which are hallmark characteristics of chronic HF [7 –9]. Most HF patients are older adults who initially seek medical attention because of an insidious history of fatigue, dyspnea, peripheral edema and/or functional decline. For older adults, many of these symptoms are commonly attributed to old age, such as dyspnea or fatigue with activity, and are dismissed as unimportant, thus masking early symptom recognition of decompensation and resulting in a delay in seeking treatment [10,11].

The purpose of this article is to review the literature focusing on aspects of HF in women including causes, biological and genetic differences, management, adherence to treatment regimens, aging and research implications. The areas of disparities are discussed as pertinent in each section of the article.

Causes of HF & contributing factors

Major causes of HF are predisposing risk factors of obesity, coronary heart disease (CHD), diabetes and hypertension (HTN) [7,12,13]. Primary CVD prevention efforts are centered on controlling these major risk factors. However, efforts have been largely unsuccessful in attenuating increases in obesity, CHD, diabetes and HTN rates, especially in ethnic minority women [2,14]. A large cross-sectional study that included 4293 women and 5082 men with diabetes evaluated treatment gender differences in primary care [15]. Male patients over 60 years of age had better diabetes and HTN control than the same age group of female patients (p < 0.01). Another study of 157,458 primary care patients with diabetes revealed that women had worse HTN control than men (p < 0.001) despite no differences between men and women's responses to antihypertensive medications [2]. In addition, women were less likely than men to have their blood pressure medications adjusted when their systolic blood pressure was elevated (p < 0.001) [16]. Lack of control of HTN increases women's risk of developing left ventricular hypertrophy (LVH) and HF.

Differences have also been noted between men and women's responses to statin therapy, used to control abnormal lipids, another major CVD risk factor. A large study was conducted with a total of 7832 men and postmenopausal women who were 40–70 years of age with abnormal lipids and no history of CHD or stroke and similar baseline total and low-density lipoprotein cholesterol levels for men and women of all age groups. Researchers reported gender differences in diet and pravastatin treatment outcomes between genders. The relative risk of CVD was reduced more markedly for women than men (relative risk was reduced by almost 30% for each age group for men and was reduced by 30% in women ≥45 years of age and by 53% in women ≥65 years of age) [17].

Perhaps one reason for women's different responses to CVD risk factors is that the biology of women's cardiovascular system is different than men's biology. This may also assist in explaining their different responses to the procedures used to diagnose CVD, CHD and HF. In fact, diagnostic tools used to diagnose, and procedures and medicines used to treat CHD, are often inadequate for women because these were developed based primarily on research conducted in men [2,18 –20]. For example, the sensitivity and specificity of the commonly used diagnostic treadmill test is lower in women than men (60–70 vs 80%) [19]. Therefore, women may not benefit equally from much of the previous research.

Another major risk factor for developing HF is CHD. Women are usually 10 or more years older than men and often have more comorbidities when they develop CHD, making it more difficult to recognize CHD symptoms in women. Symptomatology may be different, causing women to delay seeking medical care longer than men because they may experience vague symptoms, such as unusual fatigue and shortness of breath, that they may not associate with CHD. Even when women seek care, they may present with atypical chest pain or may not report experiencing any chest pain, so symptoms may not be recognized as cardiac in origin [19,21]. The severity of the illness is frequently underestimated [2,22]. Late detection of CHD contributes to worse outcomes for women, including another myocardial infarction (MI) and/or debilitating HF.

Even when diagnosed with CHD and MI, studies have shown that women are less likely to undergo cardiac catheterization and revascularization procedures than men (13.4 vs 28%) [23 –26]. This is partially attributed to the fact that women have increased microvascular disease that is not directly amenable to revascularization [27]. If women do undergo cardiac surgery, they are less likely to attend cardiac rehabilitation programs [28,29].

A systematic review of 47 clinical trials found that women with CHD were less likely to receive cardiac rehabilitation than men with CHD [30]. This is important because cardiac rehabilitation is a key secondary prevention measure that improves function, reduces disability and delays or prevents reinfarction [30]. This brief review highlights the disparities in causes, treatment and CVD outcomes between women and men that increase women's risk of developing HF.

Biological & genetic differences

Risk factors produce different biological responses in men and women. The risk of developing HF is one in five for women and men. However, at 40 years of age, the lifetime risk of developing HF without antecedent MI is one in six for women and one in nine for men [1,31]. In other words, women are more likely than men to develop HF without ischemia. In fact, the most common underlying mechanism for the development of HF in women is myocardial hypertrophy, including LVH [3], frequently resulting from poor HTN control.

HTN contributes to LVH, and this affects women and men differently. The presence of HTN more than triples the risk for HF in both genders [32], but women with HTN have a higher risk of LVH than hypertensive men [33]. Both LVH and MI cause systolic and diastolic dysfunction that can lead to HF. Left ventricular hypertrophy also makes the myocardium more susceptible to MI. This is due to several factors including:

Larger muscle mass resulting in increased demand for blood flow;

Reduced ability of the coronary circulation to vasodilate [32].

Women tend to have HF with preserved left ventricular ejection fraction (LVEF) more often than men [3,33,34]. This results in symptoms of HF, such as edema and shortness of breath, even though the LVEF is preserved. This can be caused by diastolic left ventricle dysfunction [33]; however, some postulate that other factors may contribute to HF with preserved LVEF [34]. For instance, biological processes such as anemia, renal dysfunction and diabetes can contribute to symptoms of HF without effecting diastolic function [34].

In both women and men, elevated insulin and glucose adversely affect the endothelium and lead to accelerated atherosclerosis. Insulin resistance has been linked with cardiomyopathy and cardiovascular remodeling even in the absence of hyperglycemia [35,36]. Women with diabetes are at greater risk of developing HF than diabetic men [33], partially owing to poorer control of diabetes [15]. In fact, diabetes increases women's risk of developing CVD two- to fourfold [2].

Smoking also conveys greater risk of CHD for women than men. A large meta-analysis of prospective cohort studies that included gender-specific effects of smoking on heart disease risk was recently published [37]. Results showed that after adjusting for classic cardiovascular risk factors such as total cholesterol, diabetes, blood pressure and BMI women who smoked had a 25% increased risk of CHD than men who smoked. The multiple-adjusted pooled relative risk ratio of female to male and smoking versus nonsmoking was 1.25 (95% CI: 1.12–1.39; p < 0.0001) and there was no evidence of between-study heterogeneity (p = 0.21). These findings may be influenced by biological differences between women and men.

Biological differences in HF between genders may be partially due to the hormonal activity of estrogen, testosterone or both [3,33]. These hormones affect lipid levels, vascular tone, endothelial function and patterns of adipose distribution [2]. Estrogen increases gene transcription and up regulates nitric oxide synthase in the endothelium [2]. This results in increased endothelial cell growth and may make women more resistant to vascular insults until after the menopause when estrogen levels plummet [2]. In premenopausal women, cholesterol levels are likely to be normal and adipose tissue is most often stored around the hips and thighs. After menopause, triglyceride and low-density lipoprotein levels increase and adipose tissue is more often stored along the midsection where it increases insulin resistance due to the release of cytokines into the portal circulation [2]. However, hormonal birth control methods can adversely affect lipid levels and increase young women's risk for thromboembolism and HTN.

Gene expression also differs between genders. For instance, one study analyzed gene expression in normal hearts (n = 7) and hearts in failure (n = 8) [38]. The researchers identified 162 candidate HF gene products and then examined 31 of them in a larger, more diverse population (n = 34) to evaluate the role of biological variables in gene expression. The majority of genes implicated in HF showed differences in gene expression, but most of the significant differences were due to gender and/or age, not HF alone. In fact, only five transcripts were linked to HF independently of gender or age. Another study identified unique gene-expression profiles in cardiac tissue for women (n = 6) and men (n = 5) with idiopathic dilated cardiomyopathy [39]. Female hearts demonstrated deregulation of genes associated with energy metabolism and male hearts demonstrated deregulation of genes associated with muscular contraction. A similar study of women (n = 14) and men (n = 29) with idiopathic dilated cardiomyopathy and new-onset HF also showed different gene-expression profiles in cardiac tissue between genders [40]. Some differences were on the X and Y sex chromosomes but some were not. For instance, males showed overexpression of a gene that codes for the potassium channel, which plays a role in renal potassium homeostasis. These differences in gene expression between genders may partially explain differences in HF diagnosis and response to treatment between women and men.

Management of HF in women

The ultimate goals in managing HF from both providers' and patients' perspectives are to improve quality of life and to reduce hospitalization and mortality rates using pharmacological and nonpharmacological strategies [8,9,41]. The most common pharmacological management of HF includes angiotension-converting enzyme inhibitors (ACEIs) or angiotension II receptor blockers (ARBs), β-blockers and diuretics. Nonpharmacological management includes devices and patient self-management. Treatment for HF with severe systolic dysfunction includes optimizing medications and preventing sudden cardiac death by implanting devices. The most common self-management strategies in HF for the majority of women and men are monitoring HF-related signs and symptoms, restriction of sodium and fluid intake and medication adherence. Each of these forms of treatment is discussed in the following sections.

Recommendations for pharmacological management

In the USA, the American College of Cardiology in conjunction with the American Heart Association (ACC/AHA) and the Heart Failure Society of America (HFSA) provide guidelines for the management of HF ( Table 1 ) [8,9]. The former does not provide the specified guidelines of the pharmacological management of HF in women, but the latter provides brief guidelines for women with HF.

Table 1.

Guidelines for pharmacological management of heart failure.

Medication classification	HFSA			ACC/AHA
	Patients with HF and nonpreserved LVEF†	Patients with HF and preserved LVEF‡	Special populations	Patients with HF and nonpreserved LVEF†	Patients with HF and preserved LVEF‡	Special populations
ACEIs	Part of standard therapy regardless of symptoms	May be used	Part of standard therapy for women and elderly with HF and LVSD	Part of standard therapy for patients with current or prior HF symptoms	May be used	May effect women differently than men
ARBs	Patients with intolerance to ACEIs regardless of HF symptoms; adjunct to standard therapy for patients with persistent HF symptoms; the first choice for chronic HF with reduced LVEF or HF post-MI	May be used in patients with intolerance to ACEIs	Women with HF, LVEF ≤40% and intolerance to ACEIs	Patients with current or prior HF symptoms and with intolerance to ACEIs; adjunct therapy for patients with persistent HF symptoms	May be used	–
β-blockers	Part of standard therapy for the majority of patients	Patients with prior MI, HTN or atrial fibrillation with rapid ventricular rate	Women with HF and LVSD regardless of symptoms	Part of standard therapy for stable patients	May be used	–
Diuretics	Patients with HF and fluid retention	Patients with HF and fluid retention	–	Patients with current or prior HF symptoms and fluid retention	Patients with pulmonary congestion and peripheral edema	Special attention required in women
Aldosterone antagonist	Selected patients with moderate or severe HF symptoms or post-MI	–	–	Selected patients with moderate or severe HF symptoms	–	–
Hydralazine and nitrate	Standard therapy for black patients with moderate or severe HF in addition to standard therapy; patients with intolerance to ACEIs or ARBs; as an additional treatment for patients with persistent symptoms	–	Black women with HF and moderate to severe HF symptoms	Black patients with moderate or severe symptoms on optimized standard therapy; patients with intolerance to ACEIs or ARBs; as an additional treatment for patients with persistent symptoms	–	–
Anticoagulation and antiarrhythmic agents	Patients with atrial fibrillation	–	–	–	–	Patients with concomitant disorders: atrial fibrillation or thromboembolic events
Digitalis	Adjunct treatment to standard therapy for patients with signs or symptoms of HF	–	–	Patients with current or prior HF symptoms	–	–
Calcium channel blockers	–	In selected cases including patients with atrial fibrillation, angina and HTN	–	–	May be used	–

N.B. Above pharmacological management is recommended, unless contraindicated or presence of serious side effects.

†

Reduced LVEF; ≤40%.

‡

Normal LVEF; >40%.

–: Not applicable; ACC/AHA: American College of Cardiology and American Heart Association; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; HF: Heart failure; HFSA: Heart Failure Society of America; HTN: Hypertension; LVEF: Left ventricular ejection fraction; LVSD: Left ventricular systolic dysfunction; MI: Myocardial infarction.

Data taken from [8,9].

ACEIs are recommended by both the HFSA and the ACC/AHA as part of standard therapy for patients with HF for both preserved and nonpreserved LVEF to improve left ventricular function and reduce remodeling by blocking the action of angiotensin II [8,9,42]. The HFSA guidelines are more specific for women than the ACC/AHAs are ( Table 1 ). Angiotensin II receptor antagonists can be used as an alternative to ACEIs if they are not tolerated regardless of LVEF [8,9]. In a large study that focused on HF management, the most common reason for intolerance to ACEIs in women and men was cough; women reported more coughing but had less renal dysfunction and hypotension than men [43].

β -blockers are recommended as part of standard therapy for patients with HF and nonpreserved LVEF and those with HF with preserved LVEF and prior diagnosis of MI, HTN or atrial fibrillation, β-blockers improve left ventricular function and delay the progression of HF [8,9].

Diuretics, with restriction of sodium intake, are recommended for patients with HF but there are no specific guidelines for use in women [8,9,44]. In conclusion, ACEIs/ARBs, β-blockers and diuretics are commonly recommended for patients with HF, but there is lack of specification in the guidelines for women or patients with preserved LVEF.

Impact of pharmacological management on hospitalization & mortality

Studies of patients with HF, cardiomyopathy and nonpreserved LVEF indicate that ACEIs and β-blockers reduce hospitalization and mortality rates [45 –48]. The effects of β-blockers on hospitalization and mortality rates in women were similar to, or better than, those in men [45]. In a literature review and meta-analysis of patients with HF and nonpreserved LVEF [49], the effect of ARBs on hospitalization and mortality rates were no different from those of ACEIs. The effects in HF patients with preserved LVEF were not promising. In patients with preserved LVEF (>40%) [50], hospitalization rates for HF were reduced (p = 0.047), but CVD mortality rates (p = 0.635) or a composite outcome of cardiovascular death or admission for HF and MI (p = 0.051) were not. In another study of HF patients with preserved LVEF who were prescribed ARBs [51], neither cardiovascular hospitalization nor mortality rates were reduced. However, neither of these studies analyzed data by gender. In a large retrospective study that included 10,223 women and 9475 men with HF, women receiving ARBs had better survival rates than those prescribed ACEIs (adjusted hazard ratio [HR]: 0.69; 95% CI: 0.59–0.80; p < 0.0001) and men showed no difference in survival between those prescribed ARBs and ACEIs (HR: 1.10; 95% CI: 0.95–1.30; p = 0.21) [52]. In addition, HTN was more common in women than men (50.1 vs 33.1%, respectively). The survival advantage of ARBs over ACEIs was present whether or not the women were hypertensive. However, ARBs were comparable with ACEIs in men who were hypertensive, but they were associated with worse survival rates compared with ACEIs in men who were not hypertensive. Therefore, the improved survival of women prescribed ARBs compared with ACEIs is present independently of HTN and ACEIs were found to be superior to ARBs for men with HTN and HF.

In a meta-analysis of 18 small, randomized controlled trials [53], the mortality rate in patients who were treated with diuretics was lower than that in patients who were not treated with diuretics (odds ratio: 0.25). The effects of ACEIs, β-blockers and spironolactone on hospitalization and mortality were different, depending on the type of HF [54]. In patients with nonpreserved LVEF (n = 1898; 39% women), hospitalization and mortality rates in those who were treated by ACEIs, β-blockers and spironolactone were reduced compared with those who were not treated by the medications. However, similar effects were not observed in patients with preserved LVEF (n = 1026; 64% women, who were undertreated as compared with those with nonpreserved LVEF).

Issues related to pharmacological management in women

Women are underrepresented in pharmacological trials; Greyson reports that 81% of a cross section of recent pharmaceutical studies contain no gender-based information or are gender blind [20]. Despite women comprising approximately 50% of the patients with HF and those hospitalized due to HF [1,5], the ratio of women to men in the majority of the clinical trials cited previously ranged from approximately 19 to 33% [45,46,48,49]. In fact, women comprised only 29% of subjects in a recent analysis of HF clinical trials [55]. Exclusion of patients with preserved LVEF from these studies may be one reason for the underrepresentation of women because more women have preserved LVEF than men [5]. Regardless, the underrepresentation of women in many clinical trials is extremely important as treatment guidelines are primarily based on clinical trial outcomes. Insufficient numbers of women often result in no or limited analysis by gender and may be a primary reason for the lack of specification in pharmacological management for women, despite the acknowledgement by the ACC/AHA and HFSA of the biological and physiological differences between women and men [8,9].

A second common issue related to pharmacological management in women with HF is focused on the issue of disparities in treatment between women and men. Baumhakel et al. found that evidence-based medications were underutilized in women with HF and that both the physicians' gender and the patients' gender were independent predictors of lower medication utilization in women [56]. Additional studies have documented that prescription rates of common individual HF medications were different between genders, but prescriptions for combinations of medications did not differ. For example, women were less likely to be prescribed ACEIs, anticoagulants and vasoactive medications, but were more likely to be treated with ARBs and aldosterone antagonists than men [5,57,58]. However, the combined ratios of women and men who were prescribed ACEIs/ARBs and β-blockers were similar [57 –59]. Another issue is related to the dose of medications. In one study, large percentages of HF patients did not reach the target doses of prescribed medications: ACEIs (51%), β-blockers (82%) and ARBs (91%) [59]. In addition, women, who comprised 26% of the sample, were prescribed ACEIs less often [57].

Finally, several pharmacodynamic specificities related to gender have been described in previous literature. For instance, men may experience more benefits from ACEIs, such as a reduction in hospitalizations and mortality, while women may have more benefits from ARBs as described previously [60]. Women develop digitalis toxicity and experience ACEI side effects more often than men [61]. Aspirin, which may be used for adjunctive therapy, appears to be less effective in preventing complications in women as compared with men [27]. Although the mechanisms underlying these differences are not fully known, a less effective inhibition of platelet aggregation by aspirin in women has been reported [62]. Currently, aspirin is only recommended for men and women with ischemic cardiomyopathy and for the secondary prevention of CVD; however, widespread use in patients with HF is not recommended [9]. This different response to medications for CVD and HF may be due to physiological differences, including variations in gene expression between genders but exact mechanisms are unknown [27].

Nonpharmacological management of HF: devices

Implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy [8,9,58] are commonly used for HF patients with nonpreserved LVEF to alleviate symptoms and reduce mortality [8,9,58]. However, in several ICD and cardiac resynchronization therapy studies of HF patients, women were less likely to receive a device than men [31,33,63,64]. Among 13,034 HF patients, 30% of eligible white women compared with 44% of eligible white men received ICD implantation [64]. According to Medicare data, women were significantly consistently less likely to receive cardiac resynchronization therapy than men (27 vs 73% in 2004) [65]. The findings of ICD implantation on mortality and hospitalizations were inconsistent. One ICD implantation study of 29,333 men and 25,009 women resulted in a reduction of 1-year all-cause mortality in both men (HR: 0.62) and women (HR: 0.68) after adjusting for comorbid conditions and age [63]. A second study of 293 women also indicated that ICD placement was equally efficacious in reducing risk for mortality and related hospitalization in both women and men [66]. By contrast, in a meta-analysis based on five trials (n = 934) of all-cause mortality in women who received ICDs, implantation was not significantly reduced [67]. The meta-analysis did not include the former two studies. In the study including 25,009 women, the mean age of participants was older than the other two studies. Further research is needed to examine the reasons for these conflicting findings [63].

Nonpharmacological management of HF: self-management

Common self-management activities for HF include monitoring HF-related signs and symptoms, restricting sodium and fluid intake and adhering to medications [8,9]. Providers instruct HF patients to self-monitor and report signs and symptoms [9]. Most providers recommend that HF patients weigh themselves daily and adjust their daily dose of diuretics if they have a weight gain of 2–4 pounds [9]. Patients also need to monitor and report other HF symptoms such as shortness of breath and edema. However, research indicates that few patients strictly adhere to these recommendations. For instance, in a recent study, only 14% of patients weighed themselves daily and even fewer (9%) monitored other HF symptoms [68]. In other studies, women reported not actively monitoring HF symptoms nor seeking timely treatment when symptoms occurred [69,70]. Although the use of diaries and other self-management tools have been shown to assist with self-management, adherence remains problematic [11,71].

Dietary sodium adherence rates assessed by 24-h urine collections in patients with HF remains poor overall [72]. In fact, up to 62% of hospitalizations of HF patients are related to sodium restriction nonadherence [73]. Gender-based differences may exist, as one study reported that women adhere to sodium recommendations better than men (2.7 vs 3.9 g of sodium excretion per day) and have a better understanding of the signs of fluid retention [74]. However, measurement of adherence is problematic and additional research is necessary. Both the ACC/AHA and HFSA recommend moderate sodium restriction of 2–3 g per day. In addition, both guidelines recommend restricting fluid intake to 2 1 per day for patients who experience fluid retention despite dietary sodium control and optimal pharmacological management [8,9].

HF & medication adherence

Medications for HF prolong life and alleviate many symptoms. Thus, medication adherence is a critical component of HF self-care management. Medication adherence is commonly defined as the percentage of doses that are actually taken as prescribed (proper medication, at the correct dosage and at the correct hour/time of day at least 80% of the time). However, nonadherence approaches 50% within 2 years, with a continued decline noted as a function of time [75]. Several studies report that women with HF are 18–43% less adherent than men [76,77], but findings are inconsistent across studies [75,78].

Research substantiates that medication adherence is associated with a reduced number of emergency room visits, hospitalizations and lower healthcare costs in a dose-dependent relationship (i.e., the greater the adherence, the fewer hospitalizations and the lower the individual healthcare costs) [79 –81]. However, the average number of medications required for HF treatment often reaches 11 per day, many with complex dosing schedules [79,82,83]. Consequently, women with HF who tend to be older and more likely to have more comorbidities than their male counterparts must cope with the burden of taking multiple daily medications to achieve optimal lifelong therapy, making adherence more difficult and less likely.

A lack of adherence to medical recommendations is the most commonly identified factor for acute cardiac decompensation in HF patients and, consequently, hospital admissions and rising costs. Dunlay et al. [79] and others [82,84,85] discuss the difficulty of medication adherence in rural community patients and report that out-of-pocket costs for medications were directly related to reduced adherence. Results of a recent qualitative research study indicated that older women with HF (n = 32) described an average of 7.1 barriers to medication adherence [82]. For instance, they identified medication side effects as a major barrier, but since they did not know which drug was responsible, they self-modified their entire drug regimen in an attempt to control bothersome side effects. Other common barriers they reported at 3 months postdischarge were a lack of knowledge of why the medications were prescribed, confusion of medications (especially if dosage changes occurred), scheduling barriers and worry and concern about taking their medications correctly. In this group, half of the older women wished they could talk to a provider to discuss their drug therapy side effects and other medication issues, but perceived that they did not have an opportunity to do so. Results of this study are supported by a recent review by Bosworth and colleagues who reported that barriers are prominent and emphasized that low health literacy and poor communication were key components of poor adherence [84]. A larger study of both women and men found that 67% of 495 HF patients (38% female) reported adverse medication effects within the last month, averaging three adverse medication effects per patient [86]. Of these patients, 40% felt that these side effects could not be controlled, emphasizing the importance of communication about HF medications, adverse side effects and adherence.

Identifying the determinants of continued HF symptoms or acute exacerbation in patients treated to recommended guidelines is a key factor in optimal care, yet little is known about whether providers are effectively identifying patients who are nonadherent to medications. For example, provider failure to correctly differentiate medication nonadherence from a worsening condition, such as resistant HTN, often results in intensified doses of prescribed medications to correct the perceived problem. If nonadherence is the major contributing factor to the perceived problem, this may lead to misdiagnosis, adverse events, hospitalizations and higher costs [81,87]. This distinction is critically important so that over treatment and manipulation of medications are not undertaken in those who are nonadherent, yet differentiation of adherence/nonadherence in a busy medical clinic is difficult at best. These findings emphasize the need for focused communication between the provider and HF patient to assess for medication adherence/nonadherence and to instruct patients accordingly.

In a recent study of older women with HF, women identified facilitators of medication adherence [82]. They reported key facilitators promoting medication adherence such as receiving medication counseling at hospital discharge, a pillbox system and family member assistance. Other researchers have surmised that postdischarge intervention, such as transitional care, is most likely warranted in high-risk HF patients. Providing transitional care has been shown to improve medication adherence [88], yet this intervention remains underutilized [84]. Importantly, Medicare Part D, through provisions of the Affordable Care Act, reimburses medication therapy management assistance to HF patients because these patients have complex and costly medication therapy, and often have at least two chronic diseases [101]. Assistance includes monitoring responses to therapy through telephone consultation by a pharmacist and/or other qualified provider quarterly and comprehensive medication reviews at least annually. The patient receives an individualized written summary with recommendations for monitoring, education, optimization of therapy and self-management. Unfortunately, HF patients and sometimes providers are often unaware of this invaluable service.

Aging & HF

The USA is in the midst of a longevity revolution. Older women outnumber older men, accounting for 59% of the population over 65 years of age and 68% of the population aged 85 years and over. Substantial socioeconomic disparities exist between genders during older age and women fare worse; 37.8% live at or below 200% of the US federal poverty threshold compared with 23% of males, and thus are considered economically insecure. Black older women fare worse with 49.2% living at or below 200% of the federal poverty measure [102]. Women are the largest group with HF owing to their propensity to live longer. However, in HF, lower socioeconomic status is directly associated with poorer health and lower functional capacity and higher rates of hospitalization effecting women disproportionately. A recent study using the Women's Health Initiative sample reported a 56% higher risk of hospitalization for HF in the lowest income quartile of older women compared with the highest and 21 % higher risk for incident HF hospitalization in the least well educated compared with the most [89].

Socioeconomic status is particularly salient for older women with HF because over half of older women aged 75–85 years are widows and 76% of those are aged over 85 years. Widows in the US are commonly referred to as the ‘poorest of the poor’ because they most commonly live well below the poverty level [103]. Lack of family and social support are also factors associated with poor outcomes in HF and this problem is exponentially increased in older women as compared with men because of their socioeconomic profile [11,90]. Only 42% of older women (aged 65 years and over) live with spouses compared with 72% of older men; 40% of older women compared with 19% of older men live alone. Clearly, identifying older women with HF who are also socioeconomically insecure and targeting additional supportive services to help alleviate these disparities in outcomes is indicated.

Impaired cognition is prevalent among older adults generally and specifically within the HF population. Impaired cognition is exceedingly high and thus contributes to ‘double jeopardy’ that is quite prevalent in older women [91,92]. Double jeopardy refers to multiple disparate conditions coexisting that exponentially increase the risk of poor outcomes among older women with HF, such as poverty, reduced social support and socioeconomic status and comorbidities. Impaired cognition contributes to factors that lead to poor outcomes of older women with HF by reducing decision-making capacity and complicating HF self-management in this group. Specifically, cognitive deficits interfere with the ability to recognize and respond to worsening symptoms, follow complex medication regimens and adhere to diet and fluid restrictions [92,93]. Older women report more functional limitations, anxiety and depression than men at older ages [102], thus contributing to double jeopardy situations associated with poor outcomes in those with HF [11,90,92]. We know that older adults with HF are less likely to follow evidence-based treatments for HF than other population groups [75], and is likely, in part, due to double jeopardy. Support for women diagnosed with HF with concomitant older age and multiple comorbidities is critically needed, yet minimal research has been conducted on the everyday challenges for older women who are living in the community with multiple comorbidities and HF.

Clinical & research implications

It is probable that if treatment guidelines were followed in women for the main causes of HF (e.g., obesity, CHD, diabetes and HTN), women would be less likely to develop HF and their CVD death rates would decline [2]. Because women tend to be older at diagnosis of HF and have more comorbidities than men [1,2,31], it is possible that treatments and procedures, such as ICD placement, are contraindicated more often in women. However, a tendency by providers to treat women less aggressively than men for CVD and associated diseases may be at least partially to blame for women's worse CVD outcomes [2,27].

Medication reconciliation at each office visit and/or hospitalization occurrence at the times of admission and discharge is critically important, especially for elderly patients with HF. Women with HF are particularly at risk for nonadherence due to age at time of diagnosis, multiple comorbidities requiring complex medication schedules, possible cognitive decline, lack of social support and lower socioeconomic status. Assigning a case manager to work with these at-risk older women with HF could potentially improve adherence, improve quality of life and decrease healthcare costs associated with frequent hospitalizations and clinic and emergency department visits. Providing transition counseling from the hospital to home settings is an optimal time to instigate case management. This may become even more important as healthcare institutions enter into bundled payment agreements in order to decrease healthcare costs.

Healthcare providers need to be aware of biological and genetic differences that influence women's responses to medications for HF. Following recommended HF treatment guidelines for women is essential to improve treatment outcomes. Research including equal numbers of women and men is essential and performing gender analyses in clinical trials will ultimately improve the efficacy of these guidelines for women. We also have limited information on the influence of patients' gender and age on HF intervention strategies. Research is needed to identify efficacious interventions that minimize barriers and maximize facilitators for elders with HF.

Conclusion

CVD is the main killer of women and men. Obesity, CHD, diabetes and HTN are primary causes of HF. However, there are disparities in treatment for these conditions with women often not treated to recommended standard guidelines. In addition, biology, genetics, age and socioeconomic status influence women's responses and adherence to HF treatment. Improving the treatment of women for HF could improve their CVD outcomes and reduce the impact of CVD among women.

Future perspective

This review of influential factors impacting treatment of women with HF emphasizes that there are new opportunities to improve care for these patients. In late 2011, the Centers for Medicare and Medicaid determined that intensive behavioral therapy is reasonable and necessary for the treatment of CHD and HF. Consequently, limited reimbursement is now available to help tailor a comprehensive program for these high-risk individuals [101]. It is not yet known how this and other new policies will impact HF outcomes.

The increased use of electronic health records may be instrumental in assisting providers by prompting them to follow recommended guidelines and monitoring if patients are achieving desired control of symptoms. It may also facilitate monitoring patient adherence in real time rather than during periodic clinic appointments. With the goal of reducing treatment disparities for diseases that contribute to the development of HF, federal funding agencies will demand equal representation by gender, age and race in HF and other studies so that results are applicable to a wider range of patients. Morbidity and mortality in HF should improve for women and men of all ages and races; however, this may contribute to increased expenditures related to HF and other CVDs. The AHA projects that direct medical costs between 2012 and 2030 will triple from US$309 billion to $834 billion [l]. However, medical centers and clinics will increasingly enter into bundled payment arrangements making case management oversight a cost-effective option that, hopefully, will improve patient outcomes, decrease hospitalizations and improve quality of life for HF patients.

Executive summary

Background

Cardiovascular disease is the leading cause of death of women in the USA and kills more women than the next three leading causes of death combined.

Heart failure (HF) is a debilitating and deadly chronic disease; approximately 50% of people diagnosed with HF will die within 5 years, similar to a cancer prognosis.

Biological & genetic differences

Biological differences in HF between genders could be partially due to the hormonal activity of estrogen, testosterone or both. These hormones affect lipid levels, vascular tone, endothelial function and patterns of adipose distribution.

Female hearts demonstrated deregulation of genes associated with energy metabolism and male hearts demonstrated deregulation of genes associated with muscular contraction.

Issues related to pharmacological management in women

Insufficient numbers of women in clinical trials often result in no or limited analysis by gender and may be a primary reason for the lack of specification in pharmacological management for women, despite the acknowledgement by the American College of Cardiology/American Heart Association and the Heart Failure Society of America of the biological and physiological differences between women and men.

HF & medication adherence

Medication adherence is associated with a reduced number of emergency room visits, hospitalizations and lower healthcare costs in a dose-dependent relationship (i.e., the greater the adherence, the fewer hospitalizations and the lower the individual healthcare costs).

The Affordable Care Act provides reimbursement for high-risk patients through medication therapy management, including monitoring response to therapy and comprehensive medication reviews performed quarterly by a qualified provider.

Aging & HF

Impaired cognition is exceedingly high in HF patients and interferes with their ability to recognize and respond to worsening symptoms, follow complex medication regimens and adhere to diet and fluid restrictions.

Footnotes

C Pettey's contribution to this manuscript was supported by a fellowship award from the NIH/National Institute of Nursing Research (1-F31-NR012347-01A1). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Disparities in Heart Failure and other Cardiovascular Diseases among Women

Abstract

Keywords

Causes of HF & contributing factors

Biological & genetic differences

Management of HF in women

Recommendations for pharmacological management

Impact of pharmacological management on hospitalization & mortality

Issues related to pharmacological management in women

Nonpharmacological management of HF: devices

Nonpharmacological management of HF: self-management

HF & medication adherence

Aging & HF

Clinical & research implications

Conclusion

Future perspective

Footnotes

References