Treatment of Heart Failure in African Americans: A Consensus Statement

doi: 10.1111/j.1751-7133.2009.00118.x

REVIEW PAPER

Treatment of Heart Failure in African Americans: A Consensus Statement

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espite advances in diagnosis and treatment of heart failure (HF), it remains a growing disease state in the United States, annually affecting millions of people that causes well over a million hospitalizations, contributing to more than 50,000 deaths, and consuming billions of dollars in health care spending. Although all segments of the population are affected, this growing burden of HF is especially evident in certain populations.1–3 This disease burden is further amplified by the fact that the beneficial impact of new treatment advances has been limited by slow penetration of evidence-based therapy into the broader community setting of clinical practice. This too is especially evident in certain special populations.4 Thus, the health and economic burden of HF continues to grow and affects certain underserved populations in a disproportionate manner. African Americans represent a special population of great concern. The relative incidence of HF is 50% higher in African Americans, 3% of whom have HF, compared with 2% of the general population (Figure S1).5–7 Moreover, when affected by HF, African Americans experience a unique epidemiology and different natural history. The disease occurs at an earlier age, resulting in more substantial left ventricular dysfunction and more advanced disease severity as measured by functional class. The clinical consequence is a definite increase in morbidity (measured as increased hospitalizations) and an uncertain but possibly worse effect on mortality.8 As noted in recent reviews, the reasons for this apparent greater disease burden of HF in African Americans are complex and probably relate to the interplay of several factors, including the higher prevalence and severity of imporHF and African Americans

Joseph A. Franciosa, MD; Keith C. Ferdinand, MD; Clyde W. Yancy, MD On behalf of the Consensus Statement on Heart Failure in African Americans Writing Group Address for correspondence: Joseph A. Franciosa, MD, SUNY Downstate Medical Center, 300 East 77th Street, Apartment 28-C, New York, NY 10075 E-mail: [email protected] Sponsored by The Association of Black Cardiologists, Inc. (See Appendix for Writing Group). Manuscript received July 2, 2009; accepted July 22, 2009

tant risk factors such as hypertension, diabetes, and obesity; adverse socioeconomics; disparate health care; variances in physiologic responses to cardiovascular diseases; and genetics.6–8 African Americans have been consistently underrepresented in clinical trials of HF (Table S1),9–20 and data regarding the demographics, benefits, and risks of many important therapies in this group are sparse, thus compromising the ability to make definitive statements and recommendations.11,13 For example, in the Valsartan Heart Failure Trial (Val-HeFT), only 13% of the 2178 patients randomized at US centers were African American.21 In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), approximately l% of the study population was African American.20 The Studies on Left Ventricular Dysfunction (SOLVD) and the US Carvedilol Clinical Trials program are pivotal in supporting the routine use of angiotensin-converting enzyme (ACE) inhibitors and b-blockers in all patients with HF. However, these studies included barely 600 African Americans combined, compared with nearly 10 times that number of all other patients.11,13 Despite this paucity of available data, current HF guidelines have recommendations to include spe-

cial populations (ie, African Americans) while recognizing that extrapolation of the guidelines to all populations may include unrecognized limitations.1,2,22 Given the large burden of HF in African Americans and the worrisome natural history, more focused management of HF in this group appears warranted. In particular, existing guidelines should be emphasized and amplified where warranted to more specifically address African Americans. To that end, a national panel was convened under the sponsorship of the Association of Black Cardiologists to review available evidence and make specific recommendations for the management of HF in African Americans. This multidisciplinary panel consisted of established HF cardiologists, researchers, and members of several African American medical organizations. This consensus statement is based on a thorough survey of available pertinent literature and examination of the most recent major guidelines for HF management.1,2,22 It focuses on sections of guidelines that were judged most likely to be uniquely beneficial in the management of African Americans with HF. This statement is intended for simultaneous use with other relevant guidelines, especially those for HF, hypertension, and diabetes and is not intended to abrogate january february 2010 •

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already existing (Table S2).

HF

guidelines

Overview of HF The reader should refer to the major HF guidelines and published literature for a broader discussion of HF.1,2,22 In brief, HF is a clinical syndrome caused by a variety of cardiovascular diseases that produce cardiac structural changes leading to cardiac dysfunction and eventually the well-known symptoms of HF (ie, dyspnea, fatigue, exercise intolerance, and congestion). Cardiac dysfunction usually manifests as alterations in cardiac size and geometry (ie, ventricular remodeling), which is driven by neurohormonal activation. The remodeling process initiates an inexorable cycle of worsening left ventricular function, leading to progressive cardiac enlargement, increased hemodynamic and wall stresses, mitral valve dysfunction, further maladaptive neurohormonal activation, and ventricular irritability, all of which beget progressive cardiac dysfunction, sudden cardiac death and, ultimately, end-stage HF and pump failure death. This process may be associated with impaired systolic function, as evidenced by reduced left ventricular ejection fraction (LVEF); with normal to mildly impaired LVEF with or without diastolic abnormalities; or with what is considered to be essentially preserved ejection fraction, generally defined clinically as LVEF 40%, and presumably with abnormalities of relaxation (‘‘diastolic dysfunction’’). Several approaches to classifying the patient’s stage or clinical severity of HF have been used; the most common is the New York Heart Association (NYHA) classification, which describes classes of severity based on subjective assessment of symptoms. An adjunctive and complementary approach adopted in the American College of Cardiology ⁄ American Heart Association (ACC ⁄ AHA) guidelines emphasizes disease progression from risk factors to asymptomatic cardiac abnormalities to clinical HF, classified as stages A, B, C, and D, respectively. Each of these stages has definable characteristics and recommended interventions. The goal is to 28

HF and African Americans

prevent HF development or its progression to end-stage disease (stage D) (Figure S2).1,2 The NYHA scheme is fluid and patients may vary in functional capacity, whereas the ACC ⁄ AHA model is unidirectional and patients can only progress toward greater disease severity.

HF in African Americans Etiology. As suggested by the clinical trials experience, HF in African Americans is much more commonly associated with a nonischemic etiology of left ventricular dysfunction. Hypertension is considered to be the putative disease process, but dilated cardiomyopathies and diabetes-related diseases are also common in African Americans. Coronary artery disease remains a cause of left ventricular dysfunction in African Americans, but, as an attributable cause of HF, it is strikingly less common in African Americans than in whites. The SOLVD registry was among the first databases to yield the observation that hypertension alone affects 30% of African Americans with HF as compared with 10% of whites with HF.23 Hypertension is an even more significant factor in HF with diastolic dysfunction, but this observation is not race-specific.24 Within the US Carvedilol Clinical Trials program, hypertension was thought to be the etiology of HF in more than half of African American participants and coronary artery disease the cause in approximately a third. These proportions were reversed in whites.25 The prevalence of hypertension in African Americans in the United States is among the highest in the world and is 3 times more likely to be severe, presenting in about 75% of African Americans aged 60 years or older.22,26,27 Among persons younger than 30 years of age, the likelihood of HF developing over the ensuing 20 years was 20 times as high among blacks as among whites.28 Endorgan manifestations of hypertension are strikingly more common in African Americans, with the likelihood of endstage renal disease being 2- to 3-fold greater. Because stroke rates are higher, rates of death resulting from stroke are also higher. Left ventricular hypertrophy

occurs more frequently, affecting an estimated 30% or more of all African Americans with hypertension, compared with only 10% of hypertensive whites. Notably, left ventricular hypertrophy is 2 to 3 times more likely to develop in African Americans than in whites, even when adjusted for body composition.29 In addition, the pattern of hypertrophy (ie, concentric hypertrophy) is associated with increased morbidity and mortality. Moreover, the pathophysiology of hypertension is unique in the African American as it is more commonly associated with increased sodium sensitivity, relatively low renin activity, and possibly reduced nitric oxide (NO) production.30 Based on available evidence, hypertension is a more severe illness in African Americans than in whites, and the natural history of some African Americans affected by hypertension represents a much more malignant vascular response. In addition to the greater prevalence of hypertension, African Americans are also 1.6 times more likely than whites to have diabetes.31 Thus, the higher prevalence of diabetes, hypertension, and hypertension-related end-organ damage among African Americans provides a plausible explanation for the apparent excess disease burden of HF in this population.6–8 These facts clearly mandate greater attention to the recognition and early and aggressive treatment of hypertension and diabetes in the African American population as per recommended guidelines.1,2,5,22,32 Pathophysiology of HF in African Americans. Neurohormonal activation remains the core pathophysiologic consideration in the genesis of HF in all populations. However, other pathologic mechanisms, especially differences in vascular function between African Americans and whites, may underlie the enhanced disease burden of HF in African Americans. Vascular reactivity of some African Americans may be more dependent on NO.33,34 Compared with whites, some African Americans have more exaggerated vasoconstrictor responses and less responsiveness to certain vasodilators and to inhibition of the renin-angiotensin system.35–37 january february 2010 •

Evidence suggests that abnormal endothelial function may contribute to abnormal blood pressure responses with more severe consequences in African Americans. This burden of endothelial dysfunction may result, in part, from insufficient NO secondary to reduced endothelial production of NO or to increased NO inactivation by reactive oxygen species.33–35 Abnormalities of NO production or metabolism also may contribute to adverse ventricular remodeling. As shown schematically in Figure S3, angiotensin II is a potent stimulator of cardiac and vascular remodeling, whereas NO is a potent inhibitor of this remodeling process.38 Hypothetically, the balance between these is the normal situation, and upsetting it leads to progressive remodeling. Available data now indicate potential racial differences between African Americans and whites in this imbalance of angiotensin II and NO in HF.33–35,37 In whites, according to this hypothesis, the imbalance in HF results mainly from a pronounced increase in angiotensin II, with modestly reduced NO. In African Americans with HF,37 NO may be reduced more and angiotensin II may be increased less than in whites. Disturbed homeostasis of NO represents a new direction in understanding the pathophysiology of HF and is a new target for therapeutic intervention. Aside from regulating vascular tone and blood pressure, NO inhibits vascular smooth muscle cell proliferation, adhesion of leukocytes to the endothelial surface, and platelet aggregation.39 Disruption of the NO signaling pathway (ie, endothelial dysfunction) is related to increased production of reactive oxygen species (superoxide) within the vascular wall. In addition, reactive oxygen species deplete the bioavailability of NO by reacting directly with it to produce peroxynitrate: a potent oxidant that causes further oxidative injury to the endothelium. In addition to demonstrating reduced NO bioavailability, there is also evidence that African Americans have increased oxidative stress and attenuated responsiveness to the vasodilatory effects of NO.35,40 The prevalence in African HF and African Americans

Americans of genetic polymorphisms in glutathione S-transferase enzymes and endothelial NO synthase genes, which are responsible for cellular protection against reactive oxygen species and NO destruction, supports a plausible biologic hypothesis to explain these differences in NO homeostasis.41,42

Genetic Polymorphisms. The concept of race includes multiple facets and is a grouping based on a sociopolitical designation that is neither physiologic nor scientific in its construct. As such, it is an unacceptable proxy for genetics. This is especially the case for African Americans, who represent a markedly heterogeneous admixture of other races. Nevertheless, in small data sets, certain genetic markers have been identified to exist in a linkage disequilibrium (ie, higher than expected frequency) in African Americans. It is possible that genetic variations may explain some of the pathophysiologic differences in HF in African Americans.43–51 Remarkably, several of these at-risk genotypes are associated with exaggerated development of cardiovascular disease and diminished therapeutic responsiveness. Standard methodologies now permit identification of single-nucleotide polymorphisms (SNPs) that alter gene function and protein expression, resulting in either a loss or a gain of responsiveness. Prototypical SNPs relevant to HF in African Americans have been described. It has been observed that a dual-receptor polymorphism in the b1- and a-adrenergic receptors, seen more commonly in African Americans with HF, is associated with an increased risk of HF and worse outcomes.43 This is postulated to occur as a result of an increased release of norepinephrine from the presynaptic cleft and increased sensitivity to norepinephrine. A mutation of the b3-subunit of the Gi-type protein is also overexpressed in some African Americans, and it correlates with hypertension and renal disease as well as salt sensitivity.44,45 Other SNPs have been identified in African Americans and may be implicated in the development of left ventricular dysfunction and HF. Poly-

morphisms of certain genes involving ACE have been observed and might contribute to the decreased responsiveness of African Americans to ACE inhibitors.44,46,47 Other polymorphisms that affect natriuretic peptides, b-receptors,48 and endothelin may also contribute to progressive left ventricular dysfunction in African Americans.49,50 Most recently, the Genetic Risk Assessment of Heart Failure (GRAPH) Substudy of the African American Heart Failure Trial (A-HeFT) has shown that a specific polymorphism of aldosterone synthase exists in a higher frequency in self-identified African Americans. This polymorphism at position 344 of the aldosterone synthase gene is associated with greater responsiveness to the combination of isosorbide dinitrate and hydralazine.51 These data and other preliminary findings from A-HeFT and other trials suggest that some of these genetic variants are distributed disproportionately across racial groups and that genetic screening may enable more precise targeting of patients for special management in the future. This is the promise of pharmacogenomics, but much more research is required before widespread clinical use can occur.1,2,22 Socioeconomic Factors and Quality of Care. Lower socioeconomic status and limited access to care may contribute to excess disease burden of HF in African Americans. Lower income is the usual measure of socioeconomic status, but socioeconomic status may also involve educational status, housing density, and employment status.52,53 Disparities in quality of care are a concern among health care professionals. Evidence of disparate health care is evident in the management of HF in African Americans. HF is associated with high rates of hospital readmission, especially in African Americans.53 Increased hospitalization but lower mortality rates for HF have been observed among African Americans compared with whites.54 Whereas these paradoxical results may support differences in the pathophysiology of HF in different ethnic groups, they may also relate to the quality of january february 2010 •

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care following hospital discharge because of limited access to prescribed therapy or limited adequacy of follow-up care. The relationship between recurrence of hospital admission and income (as an indicator of socioeconomic status) was assessed in more than 40,000 patients with HF, and income was found to be a significant predictor of increased hospital readmission.52 In high-risk patients with HF involved in a disease management program, there were no observed differences in quality of care between African American and white participants at baseline or throughout the 90-day study, and similar results were seen in a study in the Veterans Health Administration in which the racial gap between whites and African Americans in health care utilization was small when access to health care was equal.55,56 These examples suggest that some differences in treatment outcomes indeed may be explained by disparities in health care utilization and may support a vigorous effort to eliminate health care disparities. However, as has been observed in other cardiovascular diseases, differences in clinical outcomes between African Americans and whites are not entirely explained by socioeconomic status because other factors may be involved.57,58 These other contributing factors include delay in seeking treatment for worsening symptoms, failure to recognize symptoms, limited disease awareness, inadequate access to health care services, noncompliance with follow-up appointments, and lack of adherence to recommended treatment. Strategies to improve health care standards should include attempts to provide culturally competent care, which encourages clear communication with patients, easier access to indicated medical therapies, and utilization of performance measures.1,2

Assessment of African Americans Presenting With HF The latest major guidelines for HF management provide detailed recommendations on initial and follow-up assessments for patients with HF. The key recommendations from the ACC ⁄ 30

HF and African Americans

AHA guidelines are summarized in Table S3. Although these apply generally to all patients with HF, we wish to focus here on assessments of particular concern for African American patients.

Initial Assessment. The initial evaluation of all patients presenting with HF or suspected HF includes establishing the diagnosis, assessing severity, and clarifying the etiology of HF. Patients may present with symptoms of HF along with other conditions, including hypertension, diabetes, dyslipidemia, or angina, and they may have associated cardiac structural or functional changes. Usually, HF can be readily diagnosed by a careful history and physical examination, which elicit a history of exercise intolerance and ⁄ or evidence of circulatory congestion or a combination of these. These tenets of good care are race-blind. For the African American patient presenting with HF, it is imperative to carefully assess blood pressure and to seek evidence for target organ involvement (eg, fundoscopic changes, third and fourth heart sounds, and abnormal peripheral pulses). Following the diagnosis of HF in an African American, initial assessment should include standard diagnostic evaluations. Electrocardiography and chest radiography are routinely obtained and may provide evidence of prior myocardial infarction (MI), left ventricular hypertrophy, or cardiomegaly. Certain routine laboratory determinations are especially important in African Americans. If hypertension is present, these should include assessment of renal function and proteinuria. A search for secondary causes of hypertension is not inappropriate. The practitioner should not avoid such a search simply based on the higher prevalence of hypertension in African Americans (see details in appropriate guidelines for hypertension).5,32 In addition, blood sugar, serum lipids, and urinary microalbumin should be measured, given the increased prevalence of diabetes in African Americans. Current guidelines recommend 2dimensional echocardiography with Doppler flow studies as the best initial

assessment of cardiac structure and function in patients presenting with HF or those suspected of having HF.1,2,22 This is imperative in African Americans given the prevalence of hypertension that may have already progressed to left ventricular hypertrophy. In addition, echocardiography provides information about cardiac dimensions and geometry and left ventricular function (LVEF and shortening fraction) and may provide evidence of valvular disease or myocardial ischemia. This initial assessment is essential to establishing a baseline for following changes in remodeling. Exercise testing may be of value in some patients, but that is not unique to African Americans.1,2,22 A guide to evaluating the cause of HF is shown in Table S4. Valvular heart disease can be effectively treated with surgery, and coronary artery disease might require intervention. Hypertension must be carefully assessed in African Americans along with identification of any target-organ involvement, and common comorbidities such as diabetes must be vigorously evaluated and treated.59 Dyslipidemia must not be overlooked because it is often less well treated in African Americans. Alcohol and substance abuse, both secondary causes of cardiomyopathy, are more common in African Americans.52 Human immunodeficiency virus (HIV) represents an HF etiology of emerging importance in African Americans. The incidence of HIV infection is higher among both African American men and women, most often from sexual transmission.60,61 HIV can affect the heart in a variety of ways, including endocarditis, pericarditis, cardiac malignancy, premature atherosclerosis, and dilated cardiomyopathy, and HF associated with HIV has an especially poor prognosis.62,63 The mechanism of HIV-related cardiomyopathy is probably multifactorial, because the virus can damage cardiac myocytes and the drugs used to treat HIV infection also may be cardiotoxic.64,65 These effects of HIV drugs appear to be mediated through disruption of endothelial function, which is potentially a greater problem in the cardiovascular dysfunction of African Americans with january february 2010 •

hypertension and ⁄ or HF, as noted above.65 Follow-Up Assessments. Many of the initial clinical assessments should be followed at regular intervals at a frequency dependent on HF severity and the patient’s clinical status. Special procedures (eg, echocardiography, exercise testing) and laboratory testing (B-type natriuretic peptide) should be repeated judiciously based on clinical status. However, without a change in clinical status, these procedures are neither productive nor indicated. Functional capacity should be assessed at each visit using NYHA criteria. Exercise testing may be useful if a change in a patient’s symptoms or a discrepancy between physical findings and symptoms emerges. Assessment of volume status is particularly important in African Americans, who are more salt-sensitive and require careful volume status control for both hypertension and HF. Similarly, risk factors such as lipids and blood sugar, along with blood pressure and renal function, should be carefully and regularly monitored.

Treatment of HF in African Americans The reader should refer to the major guidelines for full treatment recommendations of HF in the general population.1,2,22 This consensus statement follows the general organization of those guidelines while focusing on treatment recommendations of special importance to African American patients at risk for HF and to those in whom HF has already developed (Figure S2). Management of Patients at Stage A. Current HF guidelines define patients in stage A as those at increased risk for HF but without current symptoms of HF and without evidence of structural heart disease. Stage A represents a critically important group because many of the risk factors can be effectively controlled and may prevent development of cardiac disease and ultimately HF. The risk factors of prime concern are hypertenHF and African Americans

sion, atherosclerotic disease, diabetes, obesity, dyslipidemia, substance abuse, and family history of cardiomyopathy. Almost all of these are amenable to treatment with lifestyle modifications and ⁄ or drugs. Hence, recognition and control of risk factors is critical to attempts at reducing the excess burden of heart disease and HF in African Americans. The key recommendations from the ACC ⁄ AHA guidelines for treatment of patients in stage A are summarized in Table S5. Control of Risk Factors. Of these several risk factors, the most important to consider for African American patients is hypertension detection and blood pressure control. Because African Americans have a higher prevalence of hypertension leading to detrimental cardiovascular and renal outcomes, there is a specific need for recommendations in this population. Adherence to both general treatment recommendations from Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and especially to those of the International Society on Hypertension in Blacks (Figure S4) is strongly advised in the management of hypertension.5,32 Lifestyle modifications for the prevention and management of hypertension, including weight reduction, adoption of the Dietary Approaches to Stop Hypertension (DASH) eating plan,66 restriction of dietary sodium, initiation of physical activity, and moderation of alcohol consumption, should be employed. Pharmacologic therapy should be initiated with thiazide diuretics as first-line therapy or combination agents that include thiazide diuretics if >10 mm Hg of systolic blood pressure lowering is indicated. Ultimately, a combination of several antihypertensive agents may be necessary for optimal control of blood pressure to a level