Robert B. Parker, Jean M. Nappi, and Larisa H. Cavallari
KEY CONCEPTS
Heart failure (HF) is a progressive clinical syndrome that can result from any changes in cardiac structure or function that impair the ability of the ventricle to fill with or eject blood. HF may be caused by an abnormality in systolic function, diastolic function, or both. The leading causes of HF are coronary artery disease and hypertension. The primary manifestations of the syndrome are dyspnea, fatigue, and fluid retention.
In response to a decrease in cardiac output, a number of compensatory responses are activated in an attempt to maintain adequate cardiac output, including activation of the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS), resulting in vasoconstriction and sodium and water retention as well as ventricular hypertrophy/remodeling. These compensatory mechanisms are responsible for the symptoms of HF and contribute to disease progression.
Our current understanding of HF pathophysiology is best described by the neurohormonal model. Activation of endogenous neurohormones including norepinephrine, angiotensin II, aldosterone, vasopressin, and numerous proinflammatory cytokines plays an important role in ventricular remodeling and the subsequent progression of HF. Importantly, pharmacotherapy targeted at antagonizing this neurohormonal activation has slowed the progression of HF and improved survival.
Most patients with symptomatic systolic heart failure (SHF) should be routinely treated with an angiotensin-converting enzyme (ACE) inhibitor, a β-blocker, and a diuretic. The benefits of these medications on slowing HF progression, reducing morbidity and mortality, and/or improving symptoms are clearly established. Patients should be treated with a diuretic if there is evidence of fluid retention. Treatment with digoxin may also be considered to improve symptoms and reduce hospitalizations.
In patients with SHF, ACE inhibitors improve survival, slow disease progression, reduce hospitalizations, and improve quality of life. The doses for these agents should be targeted at those shown in clinical trials to improve survival. When ACE inhibitors are contraindicated or not tolerated, an angiotensin II receptor blocker or the combination of hydralazine and isosorbide dinitrate is a reasonable alternative. Patients with asymptomatic left ventricular dysfunction and/or a previous myocardial infarction (MI) (Stage B of the American College of Cardiology [ACC]/American Heart Association [AHA] classification scheme) should also receive ACE inhibitors, with the goal of preventing symptomatic HF and reducing mortality.
The β-blockers carvedilol, metoprolol succinate, and bisoprolol have been shown to prolong survival, decrease hospitalizations and need for transplantation, and cause “reverse remodeling” of the left ventricle. These agents are recommended for all patients with a reduced left ventricular ejection fraction. Therapy must be instituted at low doses, with slow upward titration to the target dose.
Although chronic diuretic therapy frequently is used in HF patients, it is not mandatory. Diuretic therapy along with sodium restriction is required only in those patients with peripheral edema and/or pulmonary congestion. Many patients will need continued diuretic therapy to maintain euvolemia after fluid overload is resolved.
Digoxin does not improve survival in patients with SHF but does provide symptomatic benefits. Digoxin doses should be adjusted to achieve plasma concentrations of 0.5 to 1 ng/mL (0.6 to 1.3 nmol/L); higher plasma concentrations are not associated with additional benefits but may be associated with increased risk of toxicity.
Aldosterone antagonists, also known as mineralocorticoid receptor antagonists, reduce mortality in patients with SHF and New York Heart Association (NYHA) class II to IV symptoms and thus should be strongly considered in these patients provided that potassium and renal function can be carefully monitored. Aldosterone antagonists should also be considered soon after MI in patients with left ventricular dysfunction and either HF or diabetes.
The combination of hydralazine and nitrates improves the composite end point of mortality, hospitalizations for HF, and quality of life in African Americans receiving standard therapy. Current guidelines recommend the addition of hydralazine and nitrates to self-described African Americans with moderate to severe symptoms despite therapy with ACE inhibitors, diuretics, and β-blockers. This combination is also reasonable to consider in all patients who continue to have symptoms despite optimized therapy with an ACE inhibitor (or angiotensin receptor blocker [ARB]) and β-blocker. Hydralazine and a nitrate might be reasonable in patients unable to tolerate either an ACE inhibitor or ARB because of renal insufficiency, hyperkalemia, or possibly hypotension.
Treatment of HF with a preserved ejection fraction should be targeted at symptom reduction, causal clinical disease, and underlying basic mechanisms. Patients with HF and a preserved EF may be treated differently than those with systolic dysfunction.
INTRODUCTION
Heart failure (HF) is a progressive clinical syndrome that can result from any abnormality in cardiac structure or function that impairs the ability of the ventricle to fill with or eject blood.1 HF may be caused by an abnormality in systolic function, diastolic function, or both. Making the distinction is important because the prevalence, prognosis, and treatment of HF may be quite different depending on whether the predominant mechanism causing the symptoms is systolic or diastolic dysfunction. HF is the final common pathway for numerous cardiac disorders including those affecting the pericardium, heart valves, and myocardium. Diseases that adversely affect ventricular diastole (filling), ventricular systole (contraction), or both can lead to HF. For many years it was believed that reduced myocardial contractility, or systolic dysfunction (i.e., reduced left ventricular ejection fraction [LVEF]), was the sole disturbance in cardiac function responsible for HF. However, it is now recognized that large numbers of patients with the HF syndrome have relatively normal systolic function (i.e., normal LVEF). This is now referred to as HF with preserved LVEF (HFpEF) and is believed to be primarily due to diastolic dysfunction of the heart.1 Recent estimates suggest approximately 50% of patients with HF have preserved LVEF with disturbances in relaxation (lusitropic) properties of the heart, or diastolic dysfunction.2However, regardless of the etiology of HF, the underlying pathophysiologic process and principal clinical manifestations (fatigue, dyspnea, and often volume overload) are similar and appear to be independent of the initial cause. Historically, this disorder was commonly referred to as congestive HF; the preferred nomenclature is now HF since a patient may have the clinical syndrome of HF without having symptoms of congestion. This chapter will focus on treatment of patients with chronic HF from reduced as well as preserved LVEF. Chapter 5 will discuss the treatment of acute decompensated HF.2
EPIDEMIOLOGY
HF is an epidemic public health problem in the United States.3 Nearly 6 million Americans have HF with an additional 670,000 cases diagnosed each year.3 Unlike most other cardiovascular diseases, the incidence and prevalence of HF are increasing and are expected to continue to increase over the next few decades as the population ages. A large majority of patients with HF are elderly, with multiple comorbid conditions that influence morbidity and mortality.3Improved survival after myocardial infarction (MI) is thought to be a likely contributor to the increased incidence and prevalence of HF.4 Annual hospital discharges for HF now total over 1 million, although recent data suggest hospitalization rates are declining in the Medicare population.4 However, HF remains the most common hospital discharge diagnosis in individuals over age 65.3 The disorder also has a tremendous economic impact, with this expected to increase markedly as the baby-boom generation ages. Current estimates suggest annual expenditures for HF of approximately $39 billion, with the majority of these costs spent on hospitalized patients.5 Thus, HF is a major medical problem, with substantial economic impact that is expected to become even more significant as the population ages.
Despite prodigious advances in our understanding of the etiology, pathophysiology, and pharmacotherapy of HF, the prognosis for patients with this disorder remains grim. Although the mortality rates have declined over the last 50 years, the overall 5-year survival remains approximately 50% for all patients with a diagnosis of HF, with mortality increasing with symptom severity.3,4,6 Death is classified as sudden in about 40% of patients, implicating serious ventricular arrhythmias as the underlying cause.1 Factors affecting the prognosis of patients with HF include, but are not limited to, age, gender, LVEF, renal function, natriuretic peptide plasma concentrations, diabetes, extent of underlying coronary artery disease, blood pressure (BP), HF etiology, and drug or device therapy. Recent models incorporating these and other factors enable clinicians to develop reliable estimates of an individual patient’s prognosis.5,6
ETIOLOGY
HF can result from any disorder that affects the ability of the heart to contract (systolic function) and/or relax (diastolic dysfunction); common causes of HF are shown in Table 4-1.7 HF with reduced systolic function (i.e., reduced LVEF) is the classic, more familiar form of the disorder, but current estimates suggest up to 50% of patients with HF have preserved left ventricular systolic function with presumed diastolic dysfunction.2,8 In contrast to systolic heart failure (SHF) that is usually caused by previous MI, patients with preserved LVEF typically are elderly, female, and obese, and have hypertension (HTN), atrial fibrillation, or diabetes.8 Recent data indicate that survival is similar in patients with impaired or preserved LVEF.8
TABLE 4-1 Causes of Heart Failure
Coronary artery disease is the most common cause of SHF, accounting for nearly 70% of cases.8,9 MI leads to reduction in muscle mass due to death of affected myocardial cells. The degree to which contractility is impaired depends on the size of the infarction. To attempt to maintain cardiac output (CO), the surviving myocardium undergoes a compensatory remodeling, thus beginning the maladaptive process that initiates the HF syndrome and leads to further injury to the heart. This is discussed in greater detail in Pathophysiology below. Myocardial ischemia and infarction also affect the diastolic properties of the heart by increasing ventricular stiffness and slowing ventricular relaxation. Thus, MI frequently results in systolic and diastolic dysfunction.
Impaired systolic function is a cardinal feature of dilated cardiomyopathies. Although the cause of reduced contractility frequently is unknown, abnormalities such as interstitial fibrosis, cellular infiltrates, cellular hypertrophy, and myocardial cell degeneration are seen commonly on histologic examination. Inherited forms of dilated as well as hypertrophic cardiomyopathies may also occur.9,10
Pressure or volume overload causes ventricular hypertrophy, which attempts to return contractility to a near-normal state. If the pressure or volume overload persists, the remodeling process results in alterations in the geometry of the hypertrophied myocardial cells and is accompanied by increased collagen deposition in the extracellular matrix. Thus, both systolic and diastolic functions may be impaired.7Examples of pressure overload include systemic or pulmonary HTN and aortic or pulmonic valve stenosis.
HTN remains an important cause and/or contributor to HF in many patients, particularly women, the elderly, and African Americans.1,8 The role of HTN should not be underestimated because HTN is an important risk factor for ischemic heart disease and thus is also present in a high percentage of the patients with this disorder. HF is a largely preventable disorder such that appropriate management of lifestyle risk factors (e.g., HTN, coronary heart disease, smoking, obesity, physical activity, diabetes, etc.) is key to minimize the risk of HF development.
PATHOPHYSIOLOGY
Normal Cardiac Function
To understand the pathophysiologic processes in HF, a basic understanding of normal cardiac function is necessary. CO is defined as the volume of blood ejected per unit time (L/min) and is the product of heart rate (HR) and stroke volume (SV):
CO = HR × SV
The relationship between CO and mean arterial pressure (MAP) is:
MAP = CO × systemic vascular resistance (SVR)
HR is controlled by the autonomic nervous system. SV, or the volume of blood ejected during systole, depends on preload, afterload, and contractility.7 As defined by the Frank-Starling mechanism, the ability of the heart to alter the force of contraction depends on changes in preload. As myocardial sarcomere length is stretched, the number of cross-bridges between thick and thin myofilaments increases, resulting in an increase in the force of contraction. The length of the sarcomere is determined primarily by the volume of blood in the ventricle; therefore, left ventricular end-diastolic volume (LVEDV) is the primary determinant of preload. In normal hearts, the preload response is the primary compensatory mechanism such that a small increase in end-diastolic volume results in a large increase in CO. Because of the relationship between pressure and volume in the heart, left ventricular end-diastolic pressure (LVEDP) is often used in the clinical setting to estimate preload. The hemodynamic measurement used to clinically estimate LVEDP is the pulmonary capillary wedge pressure (PCWP), also known as the pulmonary artery occlusion pressure (PAOP). Afterload is a more complex physiologic concept that can be viewed pragmatically as the sum of forces preventing active forward ejection of blood by the ventricle. Major components of afterload are ejection impedance, wall tension, and regional wall geometry. In patients with left ventricular systolic dysfunction, an inverse relationship exists between afterload (estimated clinically by SVR) and SV such that increasing afterload causes a decrease in SV (Fig. 4-1). Contractility is the intrinsic property of cardiac muscle describing fiber shortening and tension development.
FIGURE 4-1 Relationship between stroke volume and systemic vascular resistance. In an individual with normal left ventricular (LV) function, increasing systemic vascular resistance has little effect on stroke volume. As the extent of LV dysfunction increases, the negative, inverse relationship between stroke volume and systemic vascular resistance becomes more important (B to A).
HF with a preserved ejection fraction can be defined as a condition in which myocardial relaxation and filling are impaired and incomplete. The ventricle is unable to accept an adequate volume of blood from the venous system, does not fill at low pressure, and/or is unable to maintain normal SV. In its most severe form, HFpEF results in overt symptoms of HF. In modest HFpEF, symptoms of dyspnea and fatigue occur only during stress or activity, when HR and end-diastolic volume increase. In its mildest form, HFpEF can be manifested as a slow or delayed pattern of relaxation and filling with little or no elevation in diastolic pressure and few or no cardiac symptoms. The congestive symptoms that occur with HFpEF are a manifestation of increased pulmonary venous pressures. HFpEF is caused by impaired myocardial relaxation and/or increased diastolic stiffness. When HF is caused by a predominant abnormality in diastolic function, the ventricular chamber is not enlarged, and EF may be normal or even elevated.2,11Figure 4-2 shows the pressure–volume relationship in a patient with normal versus abnormal diastolic function. Changes in the myocardium are associated with a shift upward and to the left of the pressure–volume curve, so that for any increase in LV volume, diastolic pressure rises to a much greater level than normally would occur. Clinically, patients present with reduced exercise tolerance and dyspnea when they have elevated LV diastolic pressures. Patients with HFpEF have a predominant abnormality in diastolic function, whereas patients with SHF have a predominant abnormality in systolic function of the LV.
FIGURE 4-2 Diastolic pressure–volume relationship in a normal patient (right trace) and a patient with diastolic dysfunction (left trace).
Recent data suggest that HFpEF may also be associated with abnormalities in endothelial and ventricular reserve function. During physical exertion, CO increases through integrated enhancements in venous return, contractility, HR, and peripheral vasodilation. The vasodilation that normally occurs during exercise is impaired in HFpEF. Pulmonary HTN is also a common finding. Abnormalities in each of these components of normal exercise reserve function have been identified in HFpEF and all may contribute to pathophysiology in individual patients.2
Compensatory Mechanisms in Heart Failure
HF is a progressive disorder initiated by any event that impairs the ability of the heart to contract and/or relax resulting in a decrease in CO. The index event may have an acute onset, as with MI, or the onset may be slow, as with long-standing HTN. Regardless of the index event, the decrease in CO results in activation of compensatory responses to maintain the circulation.7,10,12 These compensatory responses include: (a) tachycardia and increased contractility through sympathetic nervous system (SNS) activation, (b) the Frank-Starling mechanism, whereby an increase in preload results in an increase in SV, (c) vasoconstriction, and (d) ventricular hypertrophy and remodeling. Compensatory responses evolved to provide short-term support to maintain circulatory homeostasis after acute reductions in BP or renal perfusion. However, the persistent decline in CO in HF results in long-term activation of these compensatory responses resulting in the complex functional, structural, biochemical, and molecular changes important for the development and progression of HF. The beneficial and detrimental effects of these compensatory responses are described below and are summarized in Table 4-2.
TABLE 4-2 Beneficial and Detrimental Effects of the Compensatory Responses in Heart Failure
Tachycardia and Increased Contractility
The increase in HR and contractility that rapidly occurs in response to a drop in CO is primarily due to release of norepinephrine (NE) from adrenergic nerve terminals, although parasympathetic nervous system activity is also diminished.12 Loss of atrial contribution to ventricular filling also can occur (atrial fibrillation, ventricular tachycardia), reducing ventricular performance even more. Because ionized calcium is sequestered into the sarcoplasmic reticulum and pumped out of the cell during diastole, the shortened diastolic time with increases in HR also results in a higher average intracellular calcium concentration during diastole, increasing actin–myosin interaction, augmenting the active resistance to fibril stretch, and reducing lusitropy. Conversely, the higher average calcium concentration translates into greater filament interaction during systole, generating more tension.7 Increasing HR also increases myocardial oxygen demand. If ischemia is induced or worsened, both diastolic and systolic functions may become impaired, and SV can drop precipitously. In addition, polymorphisms in genes coding for adrenergic receptors (e.g., β1- and α2c-receptors) and their signaling pathways may affect the risk for development of HF and alter the response to endogenous NE.13
Fluid Retention and Increased Preload
Augmentation of preload is another compensatory response that is rapidly activated in response to decreased CO. Renal perfusion in HF is reduced due to both depressed CO and redistribution of blood away from nonvital organs. The kidney interprets the reduced perfusion as an ineffective blood volume, resulting in activation of the renin–angiotensin–aldosterone system (RAAS) in an attempt to maintain BP and increase renal sodium and water retention. Reduced renal perfusion and increased sympathetic tone also stimulate renin release from juxtaglomerular cells in the kidney. As shown in Figure 4-3, renin is responsible for conversion of angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II may also be generated via non–ACE-dependent pathways. Angiotensin II stimulates aldosterone release from the adrenal gland, thereby providing an additional mechanism for renal sodium and water retention. As intravascular volume increases secondary to sodium and water retention, left ventricular volume and pressure (preload) increase, sarcomeres are stretched, and the force of contraction is enhanced.7 While the preload response is the primary compensatory mechanism in normal hearts, the chronically failing heart usually has exhausted its preload reserve.7 As shown in Figure 4-4, increases in preload will increase SV only to a certain point. Once the flat portion of the curve is reached, further increases in preload will only lead to pulmonary or systemic congestion, a detrimental result.7 Figure 4-4 also shows that the curve is flatter in patients with left ventricular dysfunction. Consequently, a given increase in preload in a patient with HF will produce a smaller increment in SV than in an individual with normal ventricular function.
FIGURE 4-3 Physiology of the renin–angiotensin–aldosterone system. Renin produces angiotensin I from angiotensinogen. Angiotensin I is cleaved to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II has a number of physiologic actions that are detrimental in heart failure. Note that angiotensin II can be produced in a number of tissues, including the heart, independent of ACE activity. ACE is also responsible for the breakdown of bradykinin. Inhibition of ACE results in accumulation of bradykinin that, in turn, enhances the production of vasodilatory prostaglandins.
FIGURE 4-4 Relationship between cardiac output (shown as cardiac index which is CO/BSA) and preload (shown as pulmonary artery occlusion pressure).
Vasoconstriction and Increased Afterload
Vasoconstriction occurs in patients with HF to help redistribute blood flow away from nonessential organs to coronary and cerebral circulations to support BP, which may be reduced secondary to a decrease in CO (MAP = CO × SVR).7 A number of neurohormones likely contribute to the vasoconstriction, including NE, angiotensin II, endothelin-1 (ET-1), neuropeptide Y, urotensin II, and arginine vasopressin (AVP).7 Vasoconstriction impedes forward ejection of blood from the ventricle, further depressing CO and heightening the compensatory responses. The failing ventricle is exquisitely sensitive to changes in afterload (Fig. 4-1). Thus, increases in afterload often potentiate a vicious cycle of continued worsening and downward spiraling of the HF state.
Ventricular Hypertrophy and Remodeling
While the signs and symptoms of HF are closely associated with the items described above, the progression of HF appears to be independent of the patient’s hemodynamic status. It is now recognized that left ventricular hypertrophy and remodeling are key components in the pathogenesis of progressive myocardial failure.7 Ventricular hypertrophy is a term used to describe an increase in ventricular muscle mass. Cardiac or ventricular remodeling is a broader term describing changes in both myocardial cells and extracellular matrix that result in changes in the size, shape, structure, and function of the heart. These progressive changes in ventricular structure and function ultimately result in a change in shape of the left ventricle from an ellipse to a sphere. This change in ventricular size and shape serves to further depress the mechanical performance of the heart, increases regurgitant flow through the mitral valve, and, in turn, fuels the continued progression of remodeling. Ventricular hypertrophy and remodeling can occur in association with any condition that causes myocardial injury. The onset of the remodeling process precedes the development of HF symptoms.
Cardiac remodeling is a complex process that affects the heart at the molecular and cellular levels. Key elements in the process are shown in Figure 4-5. Collectively, these events result in progressive changes in myocardial structure and function such as cardiac hypertrophy, myocyte loss, and alterations in the extracellular matrix. The progression of the remodeling process leads to reductions in myocardial systolic and/or diastolic function that, in turn, results in further myocardial injury, perpetuating the remodeling process and the decline in left ventricular performance. Angiotensin II, NE, ET, aldosterone, vasopressin, and numerous inflammatory cytokines, as well as substances under investigation, that are activated both systemically and locally in the heart and vasculature play an important role in initiating the signal transduction cascade responsible for ventricular remodeling. Although these mediators produce harmful effects on the heart, their increased circulating and tissue concentrations are also toxic to other organs and serve as an important reminder that HF is a systemic as well as a cardiac disorder.12
FIGURE 4-5 Key components of the pathophysiology of cardiac remodeling. Myocardial injury (e.g., myocardial infarction) results in the activation of a number of hemodynamic and neurohormonal compensatory responses in an attempt to maintain circulatory homeostasis. Chronic activation of the neurohormonal systems results in a cascade of events that affect the myocardium at the molecular and cellular levels. These events lead to the changes in ventricular size, shape, structure, and function known as ventricular remodeling. The alterations in ventricular function result in further deterioration in cardiac systolic and diastolic functions that further promotes the remodeling process.
Pressure overload (and probably hormonal activation) associated with HTN produces a concentric hypertrophy (increase in the ventricular wall thickness without chamber enlargement). Conversely, eccentric left ventricular hypertrophy (myocyte lengthening with increased chamber size with minimal increase in wall thickness) characterizes the hypertrophy seen in patients with systolic dysfunction or previous MI. As the myocytes undergo change, so do various components of the extracellular matrix. For example, collagen degradation may lead to myocyte slippage, fibroblast proliferation, and increased fibrillar collagen synthesis, resulting in fibrosis and stiffening of the entire myocardium. Thus, a number of important ventricular changes that occur with remodeling include alterations in the geometry of the heart from an elliptical to a spherical shape, increases in ventricular mass (from myocyte hypertrophy), and changes in ventricular composition (especially the extracellular matrix) and volumes, all of which contribute to the impaired cardiac function. If the event producing cardiac injury is acute (e.g., MI), the ventricular remodeling process begins immediately. However, it is the progressive nature of this process that results in continual worsening of the HF state, and thus is now the major focus for identification of therapeutic targets. In fact, HF pharmacotherapy associated with decreased mortality, and/or slowing the progression of the disease, produces these effects largely by slowing or reversing ventricular remodeling, a process often referred to as reverse remodeling.
The Neurohormonal Model of Heart Failure and Therapeutic Insights It Provides
Over the years, several different paradigms have guided our understanding of the pathophysiology and treatment of HF.7 The early paradigm is often called the cardiorenal model, where the problem was viewed as excess sodium and water retention, and diuretic therapy was the main therapeutic approach. Next, the cardiocirculatory model focused on impaired CO (viewed as being due to both reduced pumping capacity of the heart and systemic vasoconstriction). Treatment strategies here focused on positive inotropes and, later, vasodilators, as the primary therapies to overcome reduced CO. While the therapeutic approaches associated with these paradigms provided some symptomatic benefits, they did little to slow progression of the disease. In fact, the detrimental effects of positive inotropic drugs on survival highlighted the inadequacy of the cardiocirculatory model to explain the progressive nature of HF.
Balanced (arterial and venous) vasodilation with ACE inhibitors was the basis for initial clinical trials with these agents. Subsequent discovery that ACE inhibitors provided benefits beyond their vasodilating effects, followed by the positive results with β-adrenergic receptor blockers and aldosterone antagonists, led to the current paradigm used to describe HF pathogenesis: the neurohormonal model.7,14 This model recognizes an initiating event (e.g., MI, long-standing HTN) that leads to decreased CO and begins the “HF state.” The problem then moves beyond the heart, and it becomes a systemic disease whose progression is mediated largely by neurohormones and autocrine/paracrine factors that drive myocyte injury, oxidative stress, inflammation, and extracellular matrix remodeling. While the former paradigms still guide us to some extent in the symptomatic management of the disease (e.g., diuretics and digoxin), it is the latter paradigm that helps us understand disease progression and, more important, the ways to slow disease progression. In the sections that follow, key neurohormones and autocrine/paracrine factors, sometimes now collectively termed biomarkers, are described with respect to their role in HF and its progression. The benefits of current and investigational drug therapies can be better understood through a solid understanding of the neurohormones they regulate/affect. Although the neurohormonal model provides a logical framework for our current understanding of HF progression and the role of various medications in attenuating this progression, it must be emphasized that this model does not completely explain HF progression. For example, drug therapies that target the neurohormonal perturbations in HF usually only slow the progressive nature of the disorder rather than completely stop it. Ongoing research will likely identify additional targets for drug therapy.
Angiotensin II
Of the neurohormones and autocrine/paracrine factors that play an important role in SHF pathophysiology, angiotensin II is probably the best understood.7,15 Although circulating angiotensin II produced from ACE activity is the most familiar route for generation of angiotensin II, recent evidence indicates that this hormone is synthesized directly in the myocardium through non–ACE-dependent pathways that also contribute to HF pathophysiology.
Angiotensin II has multiple actions that contribute to its detrimental effects in HF. It is a potent vasoconstrictor mediated by binding to the angiotensin type 1 (AT1) receptor in the vasculature and it also causes release of AVP and ET-1. Angiotensin II facilitates release of NE from adrenergic nerve terminals, heightening SNS activation. It promotes sodium retention through direct effects on the renal tubules and by stimulating aldosterone release. Its vasoconstriction of the efferent glomerular arteriole helps to maintain renal perfusion pressure in patients with severe HF or impaired renal function. Finally, angiotensin II, and many of the neurohormones released in response to angiotensin II, plays a central role in stimulating ventricular hypertrophy, remodeling, myocyte apoptosis, oxidative stress, inflammation, and alterations in the myocardial extracellular matrix. Clinical data suggest that attenuating angiotensin II–mediated effects contributes substantially to the benefits of ACE inhibitor–treated and angiotensin receptor blocker (ARB)–treated patients with SHF.15,16 The favorable effects of ACE inhibitors and ARBs on hemodynamics, symptoms, hospitalizations, quality of life, and survival highlight the importance of angiotensin II in the pathophysiology of this disorder.
Norepinephrine
As described earlier in this chapter, NE plays a central role in the tachycardia, vasoconstriction, and increased contractility and plasma renin activity in HF.12 Plasma NE concentrations are elevated in correlation with the degree of HF, and patients with the highest plasma NE concentrations have the poorest prognosis.7,17 Excessive SNS activation causes downregulation of β1-receptors, with a subsequent loss of sensitivity to receptor stimulation. Excess catecholamines increase the risk of arrhythmias and can cause myocardial cell loss by stimulating both necrosis and apoptosis. Finally, NE contributes to ventricular hypertrophy and remodeling. The detrimental effects of SNS activation are further highlighted by the clinical trials of chronic therapy with β-agonists, phosphodiesterase inhibitors, or other drugs that cause SNS activation, since these agents are uniformly associated with increased mortality. Conversely, β-blockers, ACE inhibitors, and digoxin all help to decrease SNS activation, through various mechanisms, and are beneficial in HF. Thus, it is clear that NE plays a critical role in the pathophysiology of the HF state.
Aldosterone
Aldosterone-mediated sodium retention and its key role in volume overload and edema have long been recognized as important components of the HF syndrome.18 Circulating aldosterone is increased in HF due to stimulation of its synthesis and release from the adrenal cortex by angiotensin II and due to decreased hepatic clearance from reduced hepatic perfusion. Recent studies demonstrate direct effects of aldosterone on the heart that may be even more important than sodium retention in HF pathophysiology. Chief among these is the ability of aldosterone to produce interstitial cardiac fibrosis through increased collagen deposition in the extracellular matrix of the heart. By increasing the stiffness of the myocardium, cardiac fibrosis may decrease systolic function and impair diastolic function. Current research shows that extra-adrenal production of aldosterone in the heart, kidneys, and vascular smooth muscle also contributes to the progressive nature of HF through target organ fibrosis and vascular remodeling. Induction of a systemic proinflammatory state, increased oxidative stress, wasting of soft tissues and bone, secondary hyperparathyroidism, and mineral/micronutrient dyshomeostasis are other important pathologic actions of aldosterone that directly contribute to ventricular remodeling and HF progression.19 Aldosterone also may increase the risk of ventricular arrhythmias through a number of mechanisms, including creation of reentrant circuits as a result of fibrosis, inhibition of cardiac NE reuptake, depletion of intracellular potassium and magnesium, and impairment of parasympathetic traffic. Other detrimental effects of aldosterone include insulin resistance and endothelial and baroreceptor dysfunction. Clinical trials with the aldosterone antagonists spironolactone20 and eplerenone21,22 showing significant reductions in morbidity and mortality in patients with HF provide compelling evidence of the important role of aldosterone in the initiation and progression of this syndrome.
Natriuretic Peptides
The natriuretic peptide family has three members, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP).22 Of these, BNP is the one that is most useful in the diagnosis and management of HF.23,24 BNP is synthesized and released from the ventricle in response to pressure or volume overload. BNP plasma concentrations are elevated in patients with HF functioning to increase natriuresis and diuresis and attenuate activation of the RAAS and SNS.
The development of easily performed commercial assays for BNP and the related biologically inactive peptide, NT-proBNP, resulted in widespread interest in the role of these peptides as a biomarker for prognostic, diagnostic, and therapeutic use. In patients with chronic HF, the degree of elevation in BNP levels is closely associated with increased mortality, risk of sudden death, symptoms, and hospital readmission.23,24 Accurate diagnosis of acute decompensated HF in acute care settings is often difficult since many of the symptoms (e.g., dyspnea) mimic those of other disorders such as pulmonary disease or obesity. The most well-established clinical application of BNP testing is in the urgent care setting where the BNP or NT-proBNP assay is useful when combined with clinical evaluation for differentiating dyspnea secondary to either SHF or HFpEF from other causes. The Breathing Not Properly study evaluated 452 patients with echocardiography within 30 days of an emergency department visit. Of the 452 patients, 165 (36.5%) had EF >45% (mean EF 59%).25 In the patients with preserved EF who had been admitted to the hospital for dyspnea, BNP levels were significantly lower than those found in patients with SHF (413 pg/mL vs. 821 pg/mL [119 pmol/L vs. 237 pmol/L]). However, there was considerable overlap in the BNP levels in patients with HFpEF compared with those in patients without HF, making BNP levels less useful. Furthermore, the sensitivity, specificity, and predictive accuracy of BNP levels in HFpEF are limited in part because BNP is altered by age, adiposity, gender, and other factors. Similar findings have been documented with NT-proBNP. In a study of 68 symptomatic patients with isolated HFpEF (EF >50%), NT-proBNP was significantly increased in patients with isolated HFpEF and correlated with disease severity. Compared with conventional echocardiography, Doppler imaging, and heart catheterization, NT-proBNP exhibited the best negative predictive value for detection of HFpEF.26
Much interest has focused on the benefits of serial measurement of BNP as a target to guide drug therapy, primarily diuretics. Recent studies evaluating this approach have not shown consistent improvement in long-term outcomes compared with standard medical therapy.23,24 As a result, current guidelines do not support the routine use of serial measurement of BNP in the management of chronic HF.1,27
Arginine Vasopressin
AVP is a pituitary peptide hormone that regulates renal water excretion and plasma osmolality.7,14 Plasma concentrations of AVP are elevated in patients with HF, supporting its role in the pathophysiology of this disorder. The physiologic effects of AVP are mediated through the V1a, V1b, and V2 receptors. Stimulation of these receptors by increased circulating AVP results in several maladaptive responses including: (a) increased renal free water reabsorption in the face of plasma hypoosmolality resulting in volume overload and hyponatremia; (b) increased arterial vasoconstriction that contributes to reduced CO; and (c) stimulation of remodeling by cardiac hypertrophy and extracellular matrix collagen deposition.
Given the importance of AVP in HF, recent efforts have focused on the development of AVP antagonist drugs for treatment of acute and chronic HF. By blocking the AVP receptor, these agents primarily increase free water excretion (i.e., an “aquaretic” effect). Although clinical trials with tolvaptan demonstrate improvements in acute symptoms and increases in serum sodium and urine output without affecting HR, BP, renal function, or other electrolytes, no improvements in morbidity and mortality were seen.28
Other Circulating Biomarkers
The role of other biomarkers in HF pathogenesis, risk stratification, and identification of patients at risk for developing HF, and as potential therapeutic targets is an area of extensive ongoing research.13,14,23Many of these biomarkers (e.g., ET, C-reactive protein and other inflammatory cytokines, copeptin, procalcitonin) are involved in inflammation, oxidative stress, extracellular matrix remodeling, myocyte injury and stress, and kidney injury that drive the systemic response to the failing left ventricle. It is hoped that data from investigations will lead to improved understanding of disease pathophysiology, prognosis, and targets for therapy.
Factors Precipitating/Exacerbating Heart Failure
Although significant advancements have been made in treatment, symptom exacerbation, to the point that hospitalization is required, is a common and growing problem in patients with chronic HF. Hospitalization for HF exacerbation consumes large amounts of healthcare dollars and significantly impairs the patient’s quality of life; thus, there is great interest in identifying and then remedying factors that increase the risk of decompensation. Appropriate therapy can often maintain patients in a “compensated” state, indicating that they are relatively symptom-free. However, there are many aggravating or precipitating factors that may cause a previously compensated patient to develop worsened symptoms necessitating hospitalization. Often, these precipitating factors are reversible or treatable, such that a thorough evaluation for their presence is imperative.
Cardiac events are a frequent cause of worsening HF.1,29 Myocardial ischemia and infarction are potentially reversible causes that must be carefully considered since nearly 70% of HF patients have coronary artery disease. Revascularization should be considered in appropriate patients. Atrial fibrillation occurs in up to 10% to 50% of patients with HF and is associated with increased morbidity and mortality.30,31 It can exacerbate HF through rapid ventricular response and loss of atrial contribution to ventricular filling. Conversely, HF can precipitate atrial fibrillation by increasing atrial distension from ventricular volume overload. Control of ventricular response, maintenance of sinus rhythm in appropriate patients, and prevention of thromboembolism are important elements in the treatment of HF patients with atrial fibrillation. Uncontrolled HTN is also an important contributing factor and should be treated according to current guidelines.30,31
Noncardiac events are also associated with HF decompensation. Pulmonary infections frequently cause worsening HF. Many of these events would be preventable with more widespread use of the pneumococcal and influenza vaccines. Pulmonary embolus, diabetes, worsening renal function, hypothyroidism, and hyperthyroidism should also be considered.
Nonadherence with prescribed HF medications or with dietary recommendations (e.g., sodium intake and fluid restriction) is also a common cause of HF exacerbation.29,32 Recent estimates indicate that nonadherence is an important contributor to poor outcomes and that socioeconomically disadvantaged patients appear to be disproportionately affected.
A number of drugs can precipitate or exacerbate HF by one or more of the following mechanisms: (a) negative inotropic effects; (b) direct cardiotoxicity; or (c) increased sodium and/or water retention (Table 4-3).33 The resulting symptoms are typically those associated with volume overload, but in more severe cases hypoperfusion may also be present. Nonsteroidal antiinflammatory drugs (NSAIDs) are increasingly recognized for their ability to exacerbate HF and increase risk of hospitalization and mortality through volume retention, decreased renal function, and increased BP.33
TABLE 4-3 Drugs That May Precipitate or Exacerbate Heart Failure
What should be evident is that many of the precipitating factors are preventable, particularly through appropriate healthcare professional intervention. Specifically, patient education and counseling by a pharmacist should be able to identify and address inadequate HF therapy, identify medication nonadherence, and administration of drugs or the presence of drug–drug interactions that may worsen HF (Table 4-3). A careful medication history is an important aspect of evaluating the cause(s) of HF exacerbation. Discontinuation of medications known to exacerbate HF may help prevent hospitalizations. Use of medications such as antiarrhythmic agents, particularly disopyramide, dronedarone, and flecainide, and nondihydropyridine calcium channel blockers are important precipitants of exacerbations. The widespread use of NSAIDs, particularly the nonprescription ones that many patients perceive as having a low risk of adverse effects, is also problematic and should be discouraged. The thiazolidinedione (TZD) hypoglycemic drugs, rosiglitazone and pioglitazone, cause fluid retention and weight gain that may exacerbate HF. Current guidelines indicate these agents should not be used in patients with New York Heart Association (NYHA) class III or IV HF.1 Thus, many of the factors precipitating HF exacerbations (nonadherence, inadequate/inappropriate drug therapy, uncontrolled HTN, etc.) are amenable to pharmacist intervention. Thus, the value of the pharmacist’s role in careful and repeated education of patients and monitoring of the drug regimen should not be underestimated.34,35Attention to these factors may make an important contribution to reducing the risk of hospitalization and improving the patient’s quality of life.
CLINICAL PRESENTATION
Signs and Symptoms
The primary manifestations of HF are dyspnea and fatigue, which lead to exercise intolerance, and fluid overload, which can result in peripheral edema and pulmonary congestion.1,33,36 The presence of these signs and symptoms may vary considerably from patient to patient such that some patients have dyspnea but no signs of fluid retention, whereas others may have marked volume overload with few complaints of dyspnea or fatigue. However, many patients have both dyspnea and volume overload. Clinicians should remember that symptom severity often does not correlate with the degree of LV dysfunction. Patients with a low LVEF (less than 20% to 25%) may be asymptomatic, whereas those with preserved LVEF may have significant symptoms. It is also important to note that symptoms can vary considerably over time in a given patient, even in the absence of changes in ventricular function or medications.
Pulmonary congestion arises as the left ventricle fails and is unable to accept and eject the increased blood volume that is delivered to it or if pulmonary pressures are elevated due to a stiff, nondistensible ventricle. Consequently, pulmonary venous and capillary pressures rise, leading to interstitial and bronchial edema, increased airway resistance, and dyspnea. The associated signs and symptoms may include (a) dyspnea (with or without exertion), (b) orthopnea, (c) paroxysmal nocturnal dyspnea (PND), and (d) pulmonary edema. Exertional dyspnea occurs when there is a reduction in the level of exertion that causes breathlessness. This is typically described as more breathlessness than was associated previously with a specific activity (e.g., vacuuming, stair climbing). As HF progresses, many patients eventually have dyspnea at rest.
Orthopnea is dyspnea that occurs with assumption of the supine position. It occurs within minutes of recumbency and is due to reduced pooling of blood in the lower extremities and abdomen. Orthopnea is relieved almost immediately by sitting upright and typically is prevented by elevating the head with pillows. An increase in the number of pillows required to prevent orthopnea (e.g., a change from “two-pillow” to “three-pillow” orthopnea) suggests worsening HF. Attacks of PND typically occur after 2 to 4 hours of sleep; the patient awakens from sleep with a sense of suffocation. The attacks are due to severe pulmonary and bronchial congestion, leading to shortness of breath, cough, and wheezing. The reasons these attacks occur at night are unclear but may include (a) reduced pooling of blood in the lower extremities and abdomen (as with orthopnea), (b) slow resorption of interstitial fluid from sites of dependent edema, (c) normal reduction in sympathetic activity that occurs with sleep (e.g., less support for the failing ventricle), and (d) normal depression in respiratory drive that occurs with sleep.
Rales (crackling sounds heard on auscultation) are present in the lung bases due to transudation of fluid into alveoli. The rales typically are bibasilar, but if heard unilaterally, they are usually right-sided. Rales are not present in most patients with chronic HF even though there is volume overload. This is thought to be due to a compensatory increase in lymphatic drainage. Detection of rales is usually indicative of a rapid onset of worsening HF rather than the amount of excess fluid volume. A third heart sound, or S3 gallop, is heard frequently in patients with left ventricular failure and may be due to elevated atrial pressure and altered distensibility of the ventricle.
Pulmonary edema is the most severe form of pulmonary congestion, and is caused by accumulation of fluid in the interstitial spaces and alveoli. In HF patients, it is the result of increased pulmonary venous pressure. The patient experiences extreme breathlessness and anxiety and may cough pink, frothy sputum. Pulmonary edema can be terrifying for the patient, causing a feeling of suffocation or drowning. Patients with pulmonary edema may also report any of the above-mentioned signs or symptoms of pulmonary congestion.
Systemic congestion is associated with a number of signs and symptoms. Jugular venous distension (JVD) is the simplest and most reliable sign of fluid overload. Examination of the right internal jugular vein with the patient at a 45° angle is the preferred method for assessing JVD. The presence of JVD more than 4 cm above the sternal angle suggests systemic venous congestion. In patients with mild systemic congestion, JVD may be absent at rest, but application of pressure to the abdomen will cause an elevation of JVD (hepatojugular reflux).
Peripheral edema is a cardinal finding in HF. Edema usually occurs in dependent parts of the body, and thus is seen as ankle or pedal edema in ambulatory patients, although it may be manifested as sacral edema in bedridden patients. Adults typically have a 10-lb (4.5-kg) fluid weight gain before trace peripheral edema is evident; therefore, patients with acute decompensated HF may have no clinical evidence of systemic congestion except weight gain. Body weight is thus the best short-term end point for evaluating fluid status. Nonfluid weight gain and loss of muscle mass due to cardiac cachexia are potential confounders for long-term use of weight as a marker for fluid status. Hepatomegaly and ascites are other signs of systemic congestion.
Patients with HF may exhibit signs and symptoms of low CO alone or in addition to volume overload. The primary complaint associated with hypoperfusion is fatigue. Poor appetite or early satiety may be due to limited perfusion of the GI tract. Conversely, patients with such GI complaints may simply be experiencing gut edema. Subjective measures of low CO include worsening renal function, cool extremities, altered mental status, resting tachycardia, and narrow pulse pressure.
Diagnosis
No single test is available to confirm the diagnosis of HF—it is a clinical syndrome associated with specific signs and symptoms.1,27,36 Because HF can be caused or worsened by multiple cardiac and noncardiac disorders, many of which may be treatable or reversible, accurate diagnosis is essential for development of therapeutic strategies. HF is often initially suspected in a patient based on his or her symptoms. However, signs and symptoms lack sensitivity for diagnosing HF since they are frequently found with many other disorders. Even in patients with known HF, there is poor correlation between the presence or severity of symptoms and the hemodynamic abnormality. With few exceptions, HFpEF cannot be distinguished from SHF on the basis of the history, physical examination, chest x-ray, and ECG alone. The frequency with which patients have symptoms and signs of HF on physical examination or chest x-ray is not dependent on whether they have SHF or HFpEF.37 Patients with HFpEF are often elderly, hypertensive women.37
CLINICAL PRESENTATION Heart Failure
General
• Patient presentation may range from asymptomatic to cardiogenic shock
Symptoms
• Dyspnea, particularly on exertion
• Orthopnea
• Paroxysmal nocturnal dyspnea
• Exercise intolerance
• Tachypnea
• Cough
• Fatigue
• Nocturia
• Hemoptysis
• Abdominal pain
• Anorexia
• Nausea
• Bloating
• Poor appetite, early satiety
• Ascites
• Mental status changes
• Weight gain or loss
Signs
• Pulmonary rales
• Pulmonary edema
• S3 gallop
• Cool extremities
• Pleural effusion
• Cheyne-Stokes respiration
• Tachycardia
• Narrow pulse pressure
• Cardiomegaly
• Peripheral edema
• Jugular venous distention
• Hepatojugular reflux
• Hepatomegaly
• Venous stasis changes
• Lateral displacement of apical impulse
Laboratory Tests
• BNP >100 pg/mL (>29 pmol/L)
• NT-proBNP >300 pg/mL (>35 pmol/L)
• Electrocardiogram may be normal or it could show numerous abnormalities including acute ST-T wave changes from myocardial ischemia, atrial fibrillation, bradycardia, left ventricular hypertrophy
• Serum creatinine: it may be increased due to hypoperfusion. Preexisting renal dysfunction can contribute to volume overload
• Complete blood count useful to determine if heart failure due to reduced oxygen-carrying capacity
• Chest x-ray: useful for detection of cardiac enlargement, pulmonary edema, and pleural effusions
• Echocardiogram: used to assess LV size, valve function, pericardial effusion, wall motion abnormalities, and ejection fraction
• Hyponatremia: serum sodium <130 mEq/L (<130 mmol/L) is associated with reduced survival and may indicate worsening volume overload and/or disease progression
A complete history and physical examination targeted at identifying cardiac or noncardiac disorders or behaviors that may cause or hasten HF development or progression are essential in the initial patient evaluation. However, the physical examination cannot distinguish between HF due to decreased systolic function and that due to preserved systolic function. A careful medication history should also be obtained with a focus on use of ethanol, tobacco, illicit drugs (e.g., cocaine or methamphetamine), vitamins and supplements (including herbal or “natural” supplements), NSAIDs, and antineoplastic agents (anthracyclines, cyclophosphamide, trastuzumab, imatinib).
Particular attention should be paid to cardiovascular risk factors and to other disorders that can cause or exacerbate HF such as HTN, diabetes, atrial fibrillation, dyslipidemia, tobacco use, sleep-disordered breathing, and thyroid disease. Since coronary artery disease is the cause of HF in many patients, evaluation of the possibility of coronary disease is essential, especially in men. If coronary artery disease is detected, appropriate revascularization procedures may then be considered. The patient’s volume status should be documented by assessing the body weight, JVD, and presence or absence of pulmonary congestion and peripheral edema. Laboratory testing may assist in identification of disorders that cause or worsen HF. The initial evaluation should include a complete blood count, serum electrolytes (including calcium and magnesium), assessment of renal and hepatic function, urinalysis, lipid profile, hemoglobin A1C, thyroid function tests, chest x-ray, and 12-lead ECG. There are no specific ECG abnormalities associated with HF, but findings may help detect coronary artery disease or conduction abnormalities that could affect prognosis and guide treatment decisions. Measurement of BNP or NT-proBNP may also assist in differentiating dyspnea caused by HF from other causes.
Although the history, physical examination, and laboratory tests provide important insight into the underlying cause of HF, the echocardiogram is the single most useful test in the evaluation of the patient. The echocardiogram is used to assess abnormalities in cardiac structure and function and should include evaluation of the pericardium, myocardium, and heart valves, and quantification of the LVEF to determine if systolic or diastolic dysfunction is present.
TREATMENT OF CHRONIC HEART FAILURE
Desired Outcomes
The goals of therapy in management of chronic HF are to improve the patient’s quality of life, relieve or reduce symptoms, prevent or minimize hospitalizations for exacerbations of HF, slow progression of the disease process, and prolong survival. Pharmacotherapy plays a key role in achieving these goals.1 In addition, identification of risk factors for HF development and recognition of its progressive nature have led to increased emphasis on preventing the development of this disorder. With this in mind, the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the evaluation and management of chronic HF utilize a staging system that not only recognizes the evolution and progression of the disorder but also emphasizes risk factor modification and preventive treatment strategies (Fig. 4-6).1 The four stages of this system differ from the NYHA functional classification (Table 4-4) with which most clinicians are familiar. The NYHA system is primarily intended to classify symptoms according to the clinician’s subjective evaluation and does not recognize preventive measures or the progression of the disorder. A patient’s symptoms can change frequently over a short period of time due to changes in medications, diet, intercurrent illnesses, etc. For example, a patient with ACC/AHA Stage C HF with NYHA class IV symptoms such as marked volume overload could rapidly improve to class I to II with aggressive diuretic therapy. Despite these limitations, this system can be useful for monitoring patients and is widely used in HF studies. In contrast, and consistent with the progressive nature of HF, a patient’s ACC/AHA HF stage could not improve (e.g., go from Stage C to Stage B) even though the patient’s symptoms could fluctuate from NYHA class IV to I. In addition, the ACC/AHA staging system provides a more comprehensive framework for evaluation, prevention, and treatment of HF.
FIGURE 4-6 ACC/AHA heart failure staging system. (Adapted with permission from Hunt SA, Abraham WT, Chin MH, et al. Circulation 2009; 119:e391–e479.)
TABLE 4-4 New York Heart Association Functional Classification
The general principles used to guide the treatment of SHF are based on numerous large, randomized, double-blind, multicenter trials. Until recently, no such randomized trials had been performed in patients with HFpEF. Consequently, the guidelines for the management of HFpEF are based primarily on clinical investigations in relatively small groups of patients, clinical experience, and concepts based on the knowledge and understanding of the pathophysiology of the disease process. The treatment regimen outlined in Table 4-5 applies to patients with HFpEF who have clear manifestations of congestion either at rest or with exertion. Whether treatment of asymptomatic diastolic dysfunction confers any benefit has not been demonstrated.
TABLE 4-5 Targeted Approach to Treatment of HFpEF
General Measures
The complexity of the HF syndrome necessitates a comprehensive approach to management that includes accurate diagnosis, identification and treatment of risk factors, elimination or minimization of precipitating factors, appropriate pharmacologic and nonpharmacologic therapy, and close monitoring and followup.
The first step in management of chronic HF is to determine the etiology (see Table 4-1) and/or any precipitating factors. Appropriate treatment of underlying disorders (e.g., hyperthyroidism, valvular heart disease) may obviate the need for specific HF treatment. Revascularization or antiischemic therapy in patients with coronary disease may reduce HF symptoms. Drugs that aggravate HF (see Table 4-3) should be discontinued if possible.
Restriction of physical activity reduces cardiac workload and is recommended for virtually all patients with acute congestive symptoms. However, once the patient’s symptoms have stabilized and excess fluid is removed, restrictions on physical activity are discouraged.38 Exercise training may improve quality of life and yield trends toward reduced hospitalizations and death from cardiovascular causes.34,38 Current guidelines support exercise training programs in stable patients to improve clinical status.1
Because a major compensatory response in HF is sodium and water retention, restriction of dietary sodium and fluid intake is an important lifestyle intervention. Mild (<3 g/day) to moderate (<2 g/day) sodium restriction, in conjunction with daily measurement of weight, should be implemented to minimize volume retention and allow use of lower and safer diuretic doses. The typical American diet contains 8 to 10 g of sodium per day, so most patients would need to reduce their intake by over 50%. Patients should avoid adding salt to prepared foods and eliminate foods high in sodium (e.g., salt-cured meats, salted snack foods, pickles, soups, delicatessen meats, and processed foods). In patients with hyponatremia (serum Na <130 mEq/L [<130 mmol/L]) or those with persistent volume retention despite high diuretic doses and sodium restriction, daily fluid intake should be limited to 2 L/day from all sources. However, both sodium and fluid restriction must be done with care in patients with HFpEF. Excessive restriction can lead to hypotension, low-output state, and/or renal insufficiency. Daily weights may help to assess volume status. Dietary and lifestyle factors that decrease the risk of development of CAD and HTN should be encouraged.1 Although guidelines recommend reducing sodium intake in patients with HF, proven benefits of such restriction on clinical outcomes are lacking.39 In fact, there is concern among some clinicians about the increased RAAS activity that results from sodium restriction.39
Other important general measures include patient and family counseling on the signs and symptoms of HF, detailed written instructions on the importance of appropriate medication use and compliance, activity level, diet, discharge medications, weight monitoring, continuity of care, and the need for close monitoring and followup to reinforce compliance and minimize the risk of HF exacerbations and subsequent hospitalization. These activities are now referred to as self-care and constitute an important means to improve such important outcomes as hospitalization and quality of life.40
General Approach to Treatment
The ACC/AHA treatment guidelines are organized around the four identified stages of HF, and the treatment recommendations are summarized in Figures 4-7 and 4-8.1 Clinicians are reminded that, in addition to the ACC/AHA, other cardiology professional societies publish guidelines for evaluation and treatment of HF including the Heart Failure Society of America (HFSA) and the European Society of Cardiology (ESC).27,41 Although minor differences exist between the recommendations in these guidelines, they are in general agreement in their overall approach to evaluation and treatment of SHF. In addition to chronic SHF, these guidelines now also provide thorough discussions of acute decompensated HF and management of patients with comorbid diseases often encountered in this population.
FIGURE 4-7 Treatment algorithm for patients with ACC/AHA Stage A and B heart failure. (Adapted with permission from Hunt SA, Abraham WT, Chin MH, et al. Circulation 2009; 119:e391–e479.)
FIGURE 4-8 Treatment algorithm for patients with ACC/AHA Stage C heart failure. (Adapted with permission from Hunt SA, Abraham WT, Chin MH, et al. Circulation 2009; 119:e391–e479.)
Much less objective information on the treatment of HFpEF is available. This relative paucity of evidence is reflected in guidelines for the diagnosis and management of HFpEF published by the ACC/AHA, the ESC, and the HFSA.1,27,41 In general, all three guidelines recommend treating comorbid conditions by controlling HR and BP, alleviating causes of myocardial ischemia, reducing volume, and restoring and maintaining sinus rhythm. Table 4-6summarizes the therapeutic recommendations from the HFSA.
TABLE 4-6 Evidence-Based Pharmacotherapy for Heart Failure with Preserved Ejection Fraction
A recent study showing that use of guideline-recommended treatments improves mortality in patients with SHF reinforces the importance for clinicians to be familiar with these recommendations.42 However, clinicians should also remember that these are only guidelines and that evaluation and treatment should be individualized for each patient.
As the management of HF has become increasingly complex, the development of disease management programs that use multidisciplinary teams has been studied extensively. These programs utilize several broad approaches including HF specialty clinics, home-based interventions, structured telephone support, and close patient followup. Most are multidisciplinary and may include physicians, advanced practice nurses, dieticians, and pharmacists. In general, the programs focus on optimization of drug and nondrug therapy, patient and family education and counseling, exercise and dietary advice, intense followup by telephone or home visits, improving adherence to medications and lifestyle recommendations, encouragement of self-care, and early recognition of and management of volume overload.1 Such programs have typically focused on patients with more severe HF who are at high risk for hospital admission. In general, multidisciplinary disease management programs improve quality of life and reduce HF and all-cause hospitalizations and costs, although these benefits are not consistently demonstrated in all studies.43,44
Pharmacists can play an important role in the multidisciplinary team management of HF.34,35,45 Compared with conventional treatment, pharmacist interventions, which included medication evaluation and therapeutic recommendations, patient education, and followup telephone monitoring, reduced hospitalizations for HF, adverse drug events, and medication errors. Pharmacist intervention improved use of disease-modifying medications, although this did not result in better clinical outcomes.46 A recent study found that pharmacist intervention improved medication adherence and reduced emergency department visits and hospitalizations in low-income patients with HF.45 Thus, the benefits of pharmacist involvement in the multidisciplinary care of HF patients are now apparent and should include optimizing doses of HF drug therapy, screening for drugs that exacerbate HF, monitoring for adverse drug effects and drug interactions, educating patients, and patient followup. The role of pharmacists in optimizing pharmacotherapy is underscored by the finding that HF is associated with an increased risk of experiencing adverse drug reactions.47
Treatment of Stage A Heart Failure
Patients in Stage A do not have structural heart disease or HF symptoms but are at high risk for developing HF because of the presence of risk factors (Fig. 4-7). The emphasis here is on risk factor identification and modification to prevent the development of structural heart disease and subsequent HF. Commonly encountered risk factors include HTN, dyslipidemia, diabetes, obesity, metabolic syndrome, smoking, and coronary artery disease. Although each of these disorders individually increases risk, they frequently coexist in many patients and act synergistically to foster the development of HF. Effective control of both systolic and diastolic BPs reduces the risk of developing HF by approximately 50%; thus, current HTN treatment guidelines should be followed.1 Diabetes dramatically increases the risk of developing HF and adversely affects the prognosis of patients with known HF. Appropriate diabetic control is important to minimize the risk of end-organ damage but has not been shown to affect the risk of developing HF. Appropriate management of coronary disease and its associated risk factors is also important.39,48 Although treatment must be individualized, ACE inhibitors or ARBs are recommended for HF prevention in patients with multiple vascular risk factors.1
Treatment of Stage B Heart Failure
Patients in Stage B have structural heart disease, but do not have HF symptoms (Fig. 4-7). This group includes patients with left ventricular hypertrophy, recent or remote MI, valvular disease, or reduced LVEF (less than 40%). These individuals are at risk for developing HF, and treatment is targeted at minimizing additional injury and preventing or slowing the remodeling process. In addition to the treatment measures outlined in Stage A, ACE inhibitors and β-blockers are important components of therapy. Patients with a previous MI should receive both ACE inhibitors and β-blockers, regardless of the LVEF.1Similarly, patients with a reduced LVEF and no symptoms should also receive both these agents, whether or not they have had an MI.1 ARBs are an effective alternative in patients intolerant to ACE inhibitors.1
Treatment of Stage C Heart Failure
Patients with structural heart disease and previous or current HF symptoms are classified in Stage C (Fig. 4-8). In addition to treatments in Stages A and B, most patients in Stage C should be routinely treated with three medications: a diuretic, an ACE inhibitor, and a β-blocker (see Drug Therapies for Routine Use in Patients with Stage C Systolic Heart Failure below). The benefits of these medications on slowing HF progression, reducing morbidity and mortality, and improving symptoms are clearly established. Aldosterone receptor antagonists, ARBs, digoxin, and hydralazine–isosorbide dinitrate (ISDN) are also useful in selected patients. Nonpharmacologic therapy with devices such as an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy (CRT) with a biventricular pacemaker is also indicated in certain patients in Stage C (see Nonpharmacologic Therapy below). Other general measures noted earlier are also important as is careful followup and patient education to reinforce dietary and medication compliance to prevent clinical deterioration and reduce hospitalization.1,40
Dozens of trials evaluated pharmacotherapy in patients with SHF, but few focused on patients with HFpEF. In fact, most published HF studies specifically excluded patients with preserved EF. The results of large clinical trials for treatment of HFpEF as well as important ongoing studies are summarized in Table 4-7. The hope is that these studies will provide the future basis for evidence-based treatment for HFpEF.
TABLE 4-7 Completed and Ongoing Large Clinical Trials for HFpEF
Treatment of Stage D Heart Failure
Stage D HF includes patients with refractory symptoms at rest despite maximal medical therapy and those patients who undergo recurrent hospitalizations or cannot be discharged from the hospital without special interventions. These individuals have the most advanced form of HF and should be referred to HF management programs so that specialized therapies including mechanical circulatory support, continuous IV positive inotropic therapy, and cardiac transplantation can be considered in addition to standard treatments outlined in Stages A to C.1 Discussions with the patient and family members regarding prognosis, patient priorities for minimizing symptoms versus prolonging survival, options for additional treatments, and end-of-life care should be started.1,53 A scientific statement from the AHA on decision making in advanced HF is an excellent resource on these issues.54
Management of volume status can be challenging in these patients. Restriction of sodium and fluid intake may be beneficial. High doses of diuretics, combination therapy with a loop and thiazide diuretic, or mechanical methods of fluid removal such as ultrafiltration may be required. Patients in Stage D may be less tolerant to ACE inhibitors (hypotension, worsening renal insufficiency) and β-blockers (worsening HF) as high levels of neurohormonal activation maintain circulatory homeostasis. Initiation of therapy with low doses, slow upward dose titration, and close monitoring for signs and symptoms of intolerance are essential in this group of patients. The approach to treatment of patients with Stage D HF is discussed in more detail in Chapter 5.
Nonpharmacologic Therapy
Sudden cardiac death, primarily due to ventricular tachycardia and fibrillation, is responsible for 40% to 50% of the mortality in patients with HF. In general, patients in the earlier stages with milder symptoms are more likely to die from sudden death, whereas death from pump failure is more frequent in those with advanced HF. Many of these patients have complex and frequent ventricular ectopy, although it remains unknown whether these ectopic beats contribute to the risk of malignant arrhythmias or merely serve as markers for individuals at higher risk for sudden death. Drugs that attenuate disease progression such as β-blockers and aldosterone antagonists reduce the risk of sudden death. However, although class I antiarrhythmic agents can suppress ventricular ectopy, empiric treatment with them adversely affects survival.55
Implantation of an ICD is an effective primary prevention for reducing the risk of mortality from sudden death.1 In patients with NYHA class II or III symptoms and LVEF ≤35%, the ICD was superior to amiodarone or placebo for reducing mortality.56 Importantly, this study also found that amiodarone was no more effective than placebo. Thus, this drug, because of its multiple adverse effects, drug interactions, and lack of effect on mortality, should not be used for primary prevention of sudden death. However, because of the neutral effects of amiodarone on survival, it is often used in HF patients with symptomatic atrial fibrillation to maintain sinus rhythm and/or to prevent ICD discharges. The ACC/AHA guidelines recommend the ICD for both primary and secondary prevention to improve survival in patients with current or previous HF symptoms and reduced LVEF.1 A thorough review of ICD therapy can be found in Chapter 8.
The use of CRT improves a number of important end points in selected patients with chronic SHF.57,58 Delayed electrical activation of the left ventricle, characterized on the ECG by a QRS duration that exceeds 120 milliseconds, occurs in approximately one third of patients with moderate to severe SHF. Since the left and right ventricles normally activate simultaneously, this delay results in asynchronous contraction of the ventricles, which contributes to the hemodynamic abnormalities of HF. Implantation of a specialized biventricular pacemaker to restore synchronous activation of the ventricles improves ventricular contraction and hemodynamics. Use of CRT is associated with improvements in exercise capacity, NYHA classification, quality of life, hemodynamic function, hospitalizations, and mortality.57,58The ACC/AHA guidelines recommend CRT in NYHA class III to IV patients receiving optimal medical therapy and with a QRS duration ≥120 milliseconds and LVEF ≤35%.1 However, trials published since the last guideline update show impressive benefits in patients with less severe symptoms (NYHA class I to III) and that this earlier use of CRT is associated with reverse remodeling.46,57,59 It is likely that these findings will be incorporated into the next guideline revision. Combined CRT and ICD devices are available and can be used if the patient meets the indications for both devices.
Pharmacologic Therapy
With a few notable exceptions, many of the drugs used to treat SHF are the same as those for treatment of HFpEF. However, the rationale for their use, the pathophysiologic process that is being altered by the drug, and the dosing regimen may be entirely different depending on whether the patient has SHF or HFpEF. For example, β-blockers are recommended for the treatment of both SHF and HFpEF. In HFpEF, however, β-blockers are used to decrease HR, increase diastolic duration, and modify the hemodynamic response to exercise. In SHF, β-blockers are used in the long term to increase the inotropic state and modify LV remodeling. Diuretics also are used in the treatment of both SHF and HFpEF. However, the doses of diuretics used to treat HFpEF are, in general, much smaller than those used to treat SHF. Antagonists of the RAAS are useful in lowering BP and reducing LVH. Some drugs, however, are used to treat either SHF or HFpEF, but not both. Calcium channel blockers such as diltiazem, nifedipine, and verapamil have little utility in the treatment of SHF. In contrast, each of these drugs has been proposed as being useful in the treatment of HFpEF.
Drug Therapies for Routine Use in Patients with Stage C Systolic Heart Failure
A treatment algorithm for management of patients with Stage C SHF is shown in Figure 4-8. In general, these patients should receive combined therapy with an ACE inhibitor or ARB (if ACE inhibitor intolerant) and a β-blocker, plus a diuretic if there is evidence of fluid retention. An aldosterone receptor antagonist should also be considered in selected patients.1 Initiation of digoxin therapy can be considered at any time for symptom reduction, to decrease hospitalizations, or slow ventricular response in patients with concomitant atrial fibrillation.1 Drug dosing and monitoring are summarized in Tables 4-8 and 4-9.
TABLE 4-8 Drug Dosing Table
TABLE 4-9 Drug Monitoring
Diuretics The compensatory mechanisms in HF stimulate excessive sodium and water retention, often leading to pulmonary and systemic congestion.60,61 Diuretic therapy, in addition to sodium restriction, is recommended in all patients with clinical evidence of fluid retention. Once fluid overload has been resolved, many patients require chronic diuretic therapy to maintain euvolemia. Among the drugs used to manage HF, diuretics are the most rapid in producing symptomatic benefits. However, diuretics do not prolong survival or (with the possible exception of torsemide) alter disease progression, and therefore are not considered mandatory therapy. Thus, patients who do not have fluid retention would not require diuretic therapy.
The primary goal of diuretic therapy is to reduce symptoms associated with fluid retention, improve exercise tolerance and quality of life, and reduce hospitalizations from HF. Diuretics accomplish this by decreasing pulmonary and peripheral edema through reduction of preload. Although preload is a determinant of CO, the Frank-Starling curve (see Fig. 4-4) shows that patients with congestive symptoms have reached the flat portion of the curve. A reduction in preload improves symptoms but has little effect on the patient’s SV or CO until the steep portion of the curve is reached. However, diuretic therapy must be used judiciously because overdiuresis can lead to a reduction in CO, renal perfusion, and symptoms of volume depletion.
Diuretic therapy is usually initiated in low doses in the outpatient setting, with dosage adjustments based on symptom assessment and daily body weight. Change in body weight is a sensitive marker of fluid retention or loss, and it is recommended that patients monitor their status by taking daily morning body weights. Patients who gain 1 lb/day for several consecutive days or 3 to 5 lb (1.4 to 2.3 kg) in a week should contact their healthcare provider for instructions (which often will be to increase the diuretic dose temporarily). Such action often will allow patients to prevent a decompensation that requires hospitalization. One study demonstrated a significant reduction in emergency department visits with a protocol that directed patients to self-adjust their diuretic dose based on changes in HF symptoms and daily body weight.62 Hypotension or worsening renal function (e.g., increases in serum creatinine) may be indicative of volume depletion and necessitates a reduction in the diuretic dose. Assessing volume status is particularly important before ACE inhibitor or β-blocker initiation or dose uptitration as overdiuresis may predispose patients to hypotension and other adverse effects with increases in ACE inhibitor or β-blocker doses.
In patients with HFpEF, diuretic treatment should be initiated at low doses in order to avoid hypotension and fatigue. Hypotension can be a significant problem in the treatment of HFpEF because these patients have a very steep LV diastolic pressure–volume curve such that a small change in volume causes a large change in filling pressure and CO. After the acute treatment of HFpEF has been completed, long-term treatment should include small to moderate oral doses of diuretics (furosemide 20 to 40 mg/day, chlorthalidone 25 to 100 mg, or hydrochlorothiazide 12.5 to 25 mg/day).
Thiazide Diuretics Thiazide diuretics such as hydrochlorothiazide block sodium reabsorption in the distal convoluted tubule (approximately 5% to 8% of filtered sodium). The thiazides therefore are relatively weak diuretics and infrequently are used alone in HF. However, thiazides or the thiazide-like diuretic metolazone can be used in combination with loop diuretics to promote a very effective diuresis. In addition, thiazide diuretics may be preferred in patients with only mild fluid retention and elevated BP because of their more persistent antihypertensive effects compared with loop diuretics.
Loop Diuretics Loop diuretics are usually necessary to restore and maintain euvolemia in HF. They act by inhibiting a Na–K–2Cl transporter in the thick ascending limb of the loop of Henle, where 20% to 25% of filtered sodium normally is reabsorbed. Because loop diuretics are highly bound to plasma proteins, they are not highly filtered at the glomerulus. They reach the tubular lumen by active transport via the organic acid transport pathway. Competitors for this pathway (probenecid or organic by-products of uremia) can inhibit delivery of loop diuretics to their site of action and decrease effectiveness. Loop diuretics also induce a prostaglandin-mediated increase in renal blood flow, which contributes to their natriuretic effect. Coadministration of NSAIDs blocks this prostaglandin-mediated effect and can diminish diuretic efficacy. Excessive dietary sodium intake may also reduce the efficacy of loop diuretics. Unlike thiazides, loop diuretics maintain their effectiveness in the presence of impaired renal function, although higher doses may be necessary to obtain adequate delivery of the drug to the site of action.
ACE Inhibitors ACE inhibitors are the cornerstone of pharmacotherapy for patients with SHF. By blocking the conversion of angiotensin I to angiotensin II by ACE, the production of angiotensin II and, in turn, aldosterone is decreased, but not completely eliminated.16 This decrease in angiotensin II and aldosterone attenuates many of the deleterious effects of these neurohormones that drive HF progression including ventricular remodeling, myocardial fibrosis, myocyte apoptosis, cardiac hypertrophy, NE release, vasoconstriction, and sodium and water retention.16 The endogenous vasodilator bradykinin, which is inactivated by ACE, is also increased by ACE inhibitors along with the release of vasodilatory prostaglandins and histamine.16 The precise contribution of the effects of ACE inhibitors on bradykinin and vasodilatory prostaglandins is unclear. However, the persistence of clinical benefits with ACE inhibitors despite the fact that angiotensin II and aldosterone levels return to pretreatment levels in some patients suggests this is a potentially important effect.16
Numerous placebo-controlled clinical trials involving over 7,000 patients with reduced LVEF have documented the favorable effects of ACE inhibitor therapy on symptoms, NYHA functional classification, clinical status, hospitalizations, exercise tolerance, and quality of life.16 When compared with placebo, patients treated with ACE inhibitors have fewer treatment failures, hospitalizations, and increases in diuretic dosages.16 More importantly, ACE inhibitors improve survival by 20% to 30% compared with placebo and these benefits are maintained for years with continued therapy.16 ACE inhibitors also reduce the combined risk of death or hospitalization, slow the progression of HF, and reduce the rate of reinfarction.16 The benefits of ACE inhibitor therapy are independent of the etiology of HF (ischemic vs. nonischemic) and are observed in patients with mild, moderate, or severe symptoms.
ACE inhibitors also prevent the development of HF and reduce cardiovascular risk. Enalapril decreases the risk of hospitalization for worsening HF and reduces the composite end point of death and HF hospitalization in patients with asymptomatic left ventricular dysfunction.63 In patients with established atherosclerotic vascular disease (e.g., coronary, cerebral, or peripheral circulations) and normal LVEF, ACE inhibitors reduce the development of new-onset HF and diabetes, cardiovascular death, overall mortality, MI, and stroke.64
The most common cause of SHF is ischemic heart disease, where MI results in loss of myocytes, followed by ventricular dilation and remodeling. Captopril, ramipril, and trandolapril all benefit post-MI patients whether therapy is initiated early or late after the infarct.16 Collectively, these studies indicate that ACE inhibitors administered after MI improve overall survival, decrease development of severe HF, and reduce reinfarction and HF hospitalization rates.16 The effects are most pronounced in higher-risk patients, such as those with symptomatic HF or reduced LVEF, with 20% to 30% reductions in mortality reported in these patients.16 Post-MI patients without HF symptoms or decreases in LVEF (Stage B) should also receive ACE inhibitors to prevent the development of HF and to reduce mortality.1,16
The use of ACE inhibitors in patients with chronic kidney disease is particularly relevant since it is present in 25% to 50% of HF patients and is associated with an increased risk of mortality.65 In spite of the perceived risks, ACE inhibitors are effective in patients with chronic kidney disease.66,67 Since many patients have concomitant disorders (e.g., diabetes, HTN, previous MI) that also may be favorably affected by ACE inhibitors, chronic kidney disease should not be an absolute contraindication to ACE inhibitor use in patients with left ventricular dysfunction. However, these patients should be monitored carefully for the development of worsening renal function and/or hyperkalemia with special attention to risk factors associated with this complication of ACE inhibitor therapy.1
An important practical consideration is determining the proper dose of an ACE inhibitor. Despite the overwhelming benefit demonstrated with these agents, they remain underused and underdosed.68,69 Also, for patients receiving an ACE inhibitor at hospital discharge, use significantly decreases over time and patients not prescribed ACE inhibitors at discharge were unlikely to have therapy initiated in the outpatient setting.68,69 Common reasons cited for underuse or underdosing are concerns about safety and adverse reactions to ACE inhibitors, especially in patients with chronic kidney disease or hypotension. Clinical trials establishing the efficacy of these agents titrated drug doses to a predetermined target rather than according to therapeutic response. Although data on the dose-dependent effects of ACE inhibitors in patients with HF are limited, higher doses may reduce the risk of hospitalization, but not mortality, compared with lower doses.70 In many positive trials of other HF therapies (e.g., β-blockers, aldosterone antagonists), intermediate ACE inhibitor doses were generally used as background therapy. These results emphasize that clinicians should attempt to use ACE inhibitor doses proven beneficial in clinical trials, but if these doses are not tolerated, lower doses can be used with the knowledge that it is unlikely there are differences in mortality between the high and low doses. Also, initiation of β-blocker therapy should not be delayed until target ACE inhibitor doses are achieved since the addition of a β-blocker is proven to reduce mortality, whereas that is not the case with increasing ACE inhibitor doses.
In summary, the evidence that ACE inhibitors improve symptoms, slow disease progression, and decrease mortality in patients with HF and reduced LVEF (Stage C) is unequivocal. As a result, current guidelines indicate these patients should receive ACE inhibitors, unless contraindications are present.1 The clear benefit of ACE inhibitors is also evident by the selection of these agents as a key performance measure by the Joint Commission and Centers for Medicare and Medicaid Services (CMS). This measure states that patients with left ventricular systolic dysfunction discharged from the hospital should receive ACE inhibitors unless there is documentation in the medical record of an absolute contraindication or drug intolerance.
β-Blockers There is overwhelming evidence from multiple randomized, placebo-controlled clinical trials that β-blockers reduce morbidity and mortality in patients with SHF. As such, the ACC/AHA guidelines on the management of HF recommend that β-blockers should be used in all stable patients with HF and a reduced left ventricular EF in the absence of contraindications or a clear history of β-blocker intolerance.1 Patients should receive a β-blocker even if their symptoms are mild or well controlled with diuretic and ACE inhibitor therapy. Importantly, it is not essential that ACE inhibitor doses be optimized before a β-blocker is started because the addition of a β-blocker is likely to be of greater benefit than an increase in ACE inhibitor dose.1 β-Blockers are also recommended for asymptomatic patients with a reduced left ventricular EF (Stage B) to decrease the risk of progression to HF.
β-Blockers have been studied in over 20,000 patients with SHF in placebo-controlled trials. Three β-blockers have been shown to significantly reduce mortality compared with placebo: carvedilol, metoprolol succinate (CR/XL), and bisoprolol. Each was studied in a large population with the primary end point of mortality. Carvedilol was the first β-blocker shown to improve survival in HF. In the U.S. Carvedilol Heart Failure Study, 1,094 patients were randomized to carvedilol or placebo in addition to standard therapy, including an ACE inhibitor, digoxin, and diuretic.71 The study was stopped early because of a 65% reduction in the risk of death with carvedilol. Nearly 4,000 patients were randomized to metoprolol succinate (Toprol-XL®) or placebo in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF), the largest β-blocker mortality trial to date.72 This trial was also stopped early because of a significant survival benefit with β-blockade. Specifically, metoprolol was associated with a 34% reduction in total mortality, a 41% reduction in sudden death, and a 49% reduction in death from worsening HF. Bisoprolol was studied in over 2,600 patients enrolled in the Cardiac Insufficiency Bisoprolol Study II (CIBIS II).73 The study was also stopped prematurely because of a 34% reduction in total mortality with bisoprolol compared with placebo. Bisoprolol was also associated with a 44% reduction in sudden death and a 26% reduction in death due to worsening HF. Multiple post hoc subgroup analyses of data from the MERIT-HF and CIBIS II trials suggest that the benefits of β-blockade occur regardless of HF etiology or disease severity.
The majority of participants in MERIT-HF and CIBIS II had either NYHA class II or class III SHF. The efficacy and safety of β-blockers in patients with class IV HF were examined in the Carvedilol, Prospective, Randomized, Cumulative Survival (COPERNICUS) trial.74 This trial randomized nearly 2,300 clinically stable patients who had symptoms at rest or with minimal exertion to carvedilol or placebo. Like the other studies, COPERNICUS was stopped prematurely after carvedilol produced a 35% relative reduction in mortality. Carvedilol was well tolerated in this population, with fewer participants receiving carvedilol compared with placebo requiring permanent discontinuation of study medication.
Data supporting the use of β-blockers in asymptomatic patients with left ventricular systolic dysfunction (Stage B) come from a study of carvedilol in post-MI patients with a decreased left ventricular EF.75While the primary end point of all-cause mortality or hospital admission for cardiovascular problems was similar in the carvedilol and placebo groups, carvedilol significantly reduced all-cause mortality alone compared with placebo. Cardiovascular mortality and nonfatal MI were also lower among carvedilol-treated patients.
In addition to improving survival, β-blockers have been shown to improve multiple other end points. All the large clinical trials demonstrated 15% to 20% reductions in all-cause hospitalization and 25% to 35% reductions in hospitalizations for worsening HF with β-blocker therapy.73,76,77 Studies have also shown consistent improvements in left ventricular systolic function with β-blockers, with increases in LVEF of 5 to 10 units (e.g., from an EF of 20% to 25% or 30%) after several weeks to months of therapy. β-Blockers have also been shown to decrease ventricular mass, improve the sphericity of the ventricle, and reduce systolic and diastolic volumes (left ventricular end-systolic volume and LVEDV).78,79 These effects are often collectively called reverse remodeling, referring to the fact that they return the heart toward more normal size, shape, and function.
The effects of β-blockers on symptoms and exercise tolerance varied among studies. Many studies showed improvements in NYHA functional class, patient symptom scores or quality-of-life assessments (such as the Minnesota Living with Heart Failure Questionnaire), and exercise performance, as assessed by the 6-minute walk test.76–78 Other investigators found significant reductions in mortality with β-blockers but no significant improvement in symptoms.80 As such, it is important to educate patients that β-blocker therapy is expected to positively influence disease progression and survival even if there is little to no symptomatic improvement.
Most participants in β-blocker trials were on ACE inhibitors at baseline since the benefits of ACE inhibitors were proven prior to β-blocker trials. Whether the strategy of starting a β-blocker prior to an ACE inhibitor is safe and effective was addressed in CIBIS III, in which patients with mild to moderate symptoms were randomized to initial therapy with either bisoprolol or enalapril.81 Rates of death or hospitalization were similar with the two strategies. However, the trial failed to satisfy the prespecified statistical criterion for noninferiority of initial therapy with a β-blocker compared with an ACE inhibitor. In the absence of more compelling evidence, ACE inhibitors should be started first in most patients. Initiating a β-blocker first may be advantageous for patients with evidence of excessive SNS activity (e.g., tachycardia) and may also be appropriate for patients whose renal function or potassium concentrations preclude starting an ACE inhibitor (or ARB) at that time. However, the risk for decompensation during β-blocker initiation may be greater in the absence of preexisting ACE inhibitor therapy, and careful monitoring is essential.
β-Blockers antagonize the detrimental effects of the SNS described earlier in the chapter. To this end, potential mechanisms to explain the favorable effects of β-blockers in HF include antiarrhythmic effects, attenuating or reversing ventricular remodeling, decreasing myocyte death from catecholamine-induced necrosis or apoptosis, preventing fetal gene expression, improving left ventricular systolic function, decreasing HR and ventricular wall stress thereby reducing myocardial oxygen demand, and inhibiting plasma renin release.1
Components that are critical for successful β-blocker therapy include appropriate patient selection, drug initiation and titration, and patient education. β-Blockers should be initiated in stable patients who have no or minimal evidence of fluid overload.1 While β-blockers are typically started in the outpatient setting, there are data indicating that initiation of a β-blocker prior to discharge in patients who are hospitalized for decompensated HF increases β-blocker usage compared with outpatient initiation without increasing the risk of serious adverse effects.82 However, β-blockers should not be started in patients who are hospitalized in the intensive care unit or recently required IV inotropic support. In unstable patients, other HF therapy should be optimized and then β-blocker therapy reevaluated once stability is achieved.
Initiation of a β-blocker at normal doses in patients with HF may lead to symptomatic worsening or acute decompensation owing to the drug’s negative inotropic effect. For this reason, β-blockers are listed as drugs that may exacerbate or worsen HF (see Table 4-3). To minimize the likelihood for acute decompensation, β-blockers should be started in very low doses with slow upward dose titration. β-Blocker doses should be doubled no more often than every 2 weeks, as tolerated, until the target or maximally tolerated dose is reached. According to current guidelines, target doses are those associated with reductions in mortality in placebo-controlled clinical trials.1 The starting and target doses achieved in clinical trials are described in Table 4-8. Data with both metoprolol and carvedilol suggest that HR may serve as a guide to the degree of β-blockade and that lower β-blocker doses might be considered reasonable if the reduction in HR indicates a good response to β-blocker therapy.83 In fact, it remains uncertain whether β-blocker dose or the degree of HR reduction is the optimal end point to guide dose titration and predict survival.
A recent meta-analysis of 23 randomized trials involving over 19,000 patients receiving β-blockers for HF compared HR reduction and β-blocker dose as predictors of survival.83 Overall, β-blocker treatment was associated with a 24% mortality reduction. However, trials with the largest decrease in HR (median 15 beats per minute) reported a 36% reduction in mortality, whereas trials with the smallest HR reduction (median 8 beats/min) showed only a 9% mortality reduction. Greater magnitude of HR reduction was significantly associated with greater improvement in survival. On the other hand, no relationship between β-blocker dose and magnitude of mortality decrease was found. The results from this study suggest that the degree of β-blocker–mediated reduction in resting HR, but not β-blocker dose, is associated with the magnitude of improved survival. However, the analysis is limited by its retrospective design, inability to account for other factors affecting HR (e.g., vagal activity, β-receptor pharmacogenomics), and reliance on resting HR as a surrogate marker for extent of β-blockade. Although resting HR is routinely used clinically to evaluate extent of β-blockade, it is not as accurate as inhibition of exercise HR. Whether magnitude of resting HR reduction or achievement of clinical trial doses is the optimal surrogate marker for improved outcomes with β-blockers in HF remains uncertain and may only be definitively determined by prospective trials.
Of note, the smallest commercially available tablet of bisoprolol is a scored 5-mg tablet. Since the recommended starting dose of 1.25 mg/day is not readily available, bisoprolol is the least commonly used of the three agents and, in fact, is not approved by the FDA for use in HF. Thus, therapy is generally limited to either carvedilol or metoprolol succinate, and there is no compelling evidence that one drug is superior to the other. A controlled-release formulation of carvedilol (carvedilol CR) that allows once-daily dosing is available, and pharmacokinetic studies demonstrate similar degrees of drug exposure with the controlled- and immediate-release formations of the drug.84
Good communication between the patient and healthcare provider(s) is particularly important for successful therapy. Patients should understand that dose uptitration is a long, gradual process and that achieving the target dose is important to maximize the benefits of therapy. Patients should also be aware that response to therapy may be delayed and that HF symptoms may actually worsen during the initiation period. In the event of worsening symptoms, patients who understand the potential benefits of long-term β-blocker therapy may be more likely to continue treatment.
In summary, the data provide clear evidence that β-blockers slow disease progression, decrease hospitalizations, and improve survival in SHF. β-Blockers have also been shown to improve quality of life in many patients with HF, although this is not a universal finding. Based on these data, β-blockers are recommended as standard therapy for all patients with SHF, regardless of the severity of their symptoms. Clinical trial experience shows that target β-blocker doses can be achieved in the majority of patients provided that appropriate initiation, titration, and education are implemented.
In patients with HFpEF, β-blockers may help to lower and maintain low pulmonary venous pressures by decreasing HR and increasing the duration of diastole. Tachycardia is poorly tolerated in patients with HFpEF for several reasons. First, rapid HRs cause an increase in myocardial oxygen demand and a decrease in coronary perfusion time. This can promote ischemia even in the absence of epicardial CAD. Second, incomplete relaxation between cardiac cycles may result in an increase in diastolic pressure relative to volume. Third, a rapid rate reduces diastolic filling time and ventricular filling.85 Thus, many clinicians use β-blockers (and nondihydropyridine calcium channel blockers) to prevent excessive tachycardia and produce a relative bradycardia in patients with diastolic dysfunction. However, excessive bradycardia can result in a fall of CO despite an increase in LV filling.2 Such considerations underscore the need for individualizing therapeutic interventions that affect HR. In general, it is not necessary to start at an extremely low dose and titrate the β-blocker in a slow, progressive fashion in HFpEF as it is in SHF. However, because patients tend to be older, have numerous comorbidities, and take many concomitant medications, it is prudent to start with a moderate dose of β-blockers. A randomized, multicenter, open-label trial is ongoing to examine the effects of β-blocker therapy on clinical outcomes in patients with HF and a preserved left ventricular EF.86
Drug Therapies to Consider for Selected Patients
Angiotensin II Receptor Blockers The crucial role of the RAAS in HF development and progression is well established as are the benefits of inhibiting this system with ACE inhibitors. ACE inhibitors decrease angiotensin II production in the short term, but these agents do not completely suppress generation of this hormone. With chronic administration of ACE inhibitors, ACE escape, characterized by increases in circulating angiotensin II and aldosterone, often occurs.7,16 In addition, angiotensin II can be formed in a number of tissues, including the heart, through non–ACE-dependent pathways (e.g., chymase, cathepsin, and kallikrein).7,16 Therefore, blockade of the detrimental effects of angiotensin II by ACE inhibition is incomplete. By blocking the angiotensin II receptor subtype, AT1, ARBs attenuate the deleterious effects of angiotensin II on ventricular remodeling, regardless of the site of origin of the hormone. Since ARBs do not inhibit the ACE enzyme, these agents do not affect bradykinin, which is linked to ACE inhibitor cough. Because bradykinin-related adverse effects of ACE inhibitors such as angioedema and cough lead to drug discontinuation in some patients, the potential for an ARB to produce similar clinical benefits with fewer side effects is of great interest.
Although a number of ARBs are currently available, the primary clinical trials supporting the use of these agents in SHF used either valsartan or candesartan.80 The addition of valsartan to standard background HF therapy did not improve mortality but did reduce hospitalizations due to HF.87 In post-MI patients, valsartan was noninferior to captopril for reducing mortality and the combination of valsartan and captopril only increased the risk of adverse effects and did not improve survival compared with monotherapy with either agent.88 Based on these findings, valsartan is now approved for use in patients with NYHA class II to IV HF as well as post-MI patients with left ventricular dysfunction.
The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trials were designed as three studies to evaluate candesartan in patients with symptomatic HF.89 Both the CHARM-Added (patients receiving background ACE inhibitor therapy)90 and CHARM-Alternative (patients intolerant of ACE inhibitor therapy)91 trials found significant reductions in the primary end point of CV death or hospitalization for HF in patients receiving candesartan, although the benefit was modest in CHARM-Added (17% reduction). Overall, candesartan was well tolerated but its use was associated with an increased risk of hypotension, hyperkalemia, and renal dysfunction. On the basis of these results, candesartan is now approved for use in symptomatic HF in patients with LVEF ≤40% to reduce cardiovascular death and reduce HF hospitalizations.
The effect of high-dose compared with low-dose losartan treatment was evaluated in the Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan (HEAAL) study.92 Over 3,800 patients receiving standard background HF treatment who were intolerant to ACE inhibitors with a LVEF ≤40% and NYHA class II to IV symptoms were randomly assigned to losartan 50 or 150 mg daily. The higher losartan dose was associated with significant reductions (∼10%) in the primary end point of death or hospital admission for HF. Significant increases in renal insufficiency, hyperkalemia, and hypotension were also associated with the higher dose, but the development of these adverse effects did not result in increased rates of drug discontinuation. The benefits of higher ARB doses were also seen in a recent registry-based study comparing the effects of losartan and candesartan on mortality in patients with SHF.93 Overall, there were no differences in mortality in patients treated with losartan compared with that in patients treated with candesartan. However, in patients receiving low doses of losartan (12.5 to 50 mg daily), mortality was higher than in the candesartan group. High-dose losartan (100 mg daily) was equivalent to higher doses of candesartan. High-dose candesartan was superior to lower doses. These findings point out the importance of titrating the doses of these medications to the targets achieved in clinical trials.
Although ACE inhibitors remain first-line therapy in patients with Stage C SHF, the current guidelines recommend the use of ARBs in patients who are unable to tolerate (usually due to cough) ACE inhibitors.1,27,41 Caution should be exercised when ARBs are used in patients with angioedema from ACE inhibitors as some cross-reactivity is reported.94 ARBs are not an alternative in patients with hypotension, hyperkalemia, or renal insufficiency secondary to ACE inhibitors because they are as likely to cause these adverse effects. Also, the combined use of ACE inhibitors, ARBs, and aldosterone antagonists is not recommended because of the increased risk of renal dysfunction and hyperkalemia.1 The specific drugs and doses proven to be effective in clinical trials should be used (Table 4-8).
Combination therapy with an ACEI inhibitor and an ARB remains controversial. The CHARM-Added trial found the addition of candesartan to ACE inhibitor and β-blocker therapy produced incremental reductions in cardiovascular death and hospitalizations for HF, but did not improve overall survival.90 In contrast, neither the VALIANT nor the Val-HeFT trials found additional benefit from the addition of valsartan to ACE inhibitor treatment.87,88 Moreover, a recent meta-analysis showed that combination therapy is associated with increased risk of medication discontinuation due to adverse effects, hyperkalemia, renal insufficiency, and hypotension.95Collectively, these results suggest the addition of an ARB to optimal HF therapy (ACE inhibitors, β-blockers, diuretics, etc.) offers, at best, marginal benefits with increased risk of adverse effects. The ACC/AHA guidelines recommend the addition of an ARB can be considered in patients who remain symptomatic despite receiving conventional HF pharmacotherapy. Some clinicians suggest that the addition of an aldosterone antagonist to ACE inhibitor and β-blocker therapy in patients with persistent symptoms is preferred over an ARB. Unlike ARBs, combination aldosterone antagonist and ACE inhibitor therapy improves survival in patients with NYHA class II–IV HF (RALES and EMPHASIS trial) and in post-MI patients with LV systolic dysfunction (EPHESUS trial), supports this approach.20–22
The role of ARBs in the treatment of HFpEF is less clear. The CHARM-Preserved trial was the first large prospective study to demonstrate some benefit (reduction in hospitalizations for HF) of an ARB in patients with HFpEF receiving standard background treatment, although no improvement in cardiovascular death was observed.96 Adverse effects of candesartan in this study were frequent; 22% of candesartan-treated patients discontinued therapy because of hypotension, increased serum creatinine, or hyperkalemia. In the Irbesartan in Heart Failure with Preserved EF (I-PRESERVE) trial, irbesartan was compared with placebo in over 4,000 patients with symptoms of HF and a LVEF of at least 45% (0.45).97 There was no significant difference between irbesartan and placebo with regard to death or hospitalization for cardiovascular causes. No benefit was seen in quality-of-life measures. There was a high discontinuation rate of the study drug in this trial (33%), as well as a high rate of postrandomization initiation of ACE inhibitors (20%) and spironolactone (10%), which may have contributed to the outcome in this trial.
Aldosterone Antagonists 
Spironolactone and eplerenone are aldosterone antagonists that work by blocking the mineralocorticoid receptor, the target site for aldosterone, and, thus, they are also referred to as mineralocorticoid receptor antagonists. In the kidney, aldosterone antagonists inhibit sodium reabsorption and potassium excretion. While the diuretic effects with low doses of aldosterone antagonists are minimal, the potassium-sparing effects can have significant consequences as discussed below. In the heart, aldosterone antagonists inhibit cardiac extracellular matrix and collagen deposition, thereby attenuating cardiac fibrosis and ventricular remodeling.98 Aldosterone antagonists also attenuate the systemic proinflammatory state, atherogenesis, and oxidative stress caused by aldosterone. In addition, there is evidence that aldosterone antagonists may attenuate aldosterone-induced calcium excretion and reductions in bone mineral density and protect against fractures in HF.99 While spironolactone historically has been viewed as a diuretic, this is believed to contribute little to its benefits in HF, in part, because the doses used have minimal diuretic effect.20 Thus, as with ACE inhibitors and β-blockers, the data on aldosterone antagonists also support the neurohormonal model of HF.
Three large, randomized controlled trials have evaluated low-dose aldosterone antagonism in patients with either HF or post-MI and left ventricular dysfunction. All three trials excluded patients with significant renal dysfunction (e.g., serum creatinine above 2.5 mg/dL [221 μmol/L]) and elevated serum potassium (e.g., above 5 mEq/L [5 mmol/L]) at baseline.
The RALES randomized over 1,600 patients with current or recent NYHA class IV HF to aldosterone blockade with spironolactone 25 mg/day or placebo.20 Patients were also treated with standard therapy, usually including an ACE inhibitor, loop diuretic, and digoxin. Those with a serum creatinine concentration above 2.5 mg/dL (221 μmol/L) or a serum potassium concentration above 5 mEq/L (5 mmol/L) were excluded. The study was stopped prematurely after an average followup of 24 months because of a significant 30% reduction in the primary end point of total mortality with spironolactone. Spironolactone reduced mortality due to both progressive HF and sudden cardiac death. It also produced a 35% reduction in hospitalizations for worsening HF and significant symptomatic improvement, as assessed by changes in NYHA functional class. The low dose of spironolactone was well tolerated in RALES. The most common adverse effect was gynecomastia, which occurred in 10% of men on spironolactone compared with 1% of men on placebo, and led to treatment discontinuation in 2% of patients. There were statistically (but not clinically) significant increases in serum creatinine (by 0.05 to 0.10 mg/dL [4 to 9 μmol/L]) and potassium concentrations (by 0.30 mEq/L [0.30 mmol/L]) with spironolactone. The incidence of serious hyperkalemia (>6 mEq/L [>6 mmol/L]) was minimal and did not differ between spironolactone- and placebo-treated groups.
The EPHESUS trial evaluated the effect of selective antagonism of the mineralocorticoid receptor with eplerenone in patients with left ventricular dysfunction after MI.21 To be eligible for study participation, patients had to have evidence of either HF or diabetes. Over 6,600 patients were randomized within 3 to 14 days of MI to eplerenone, titrated to 50 mg/day, or placebo in addition to standard therapy, which usually included an ACE inhibitor, β-blocker, aspirin, and diuretics. Treatment with eplerenone was associated with a significant 15% relative reduction in the risk for death from any cause and a 15% reduction in the risk of hospitalization from HF. Serious hyperkalemia occurred in 5.5% of eplerenone-treated patients and 3.9% of placebo-treated patients.
Most recently, the EMPHASIS-HF trial demonstrated significant improvements in clinical outcomes with aldosterone antagonism in mild HF.22 Over 2,700 patients with NYHA class II HF and a LVEF of 35% or less were randomized to eplerenone up to 50 mg/day (mean dose of 39 mg/day) or placebo, in addition to receiving treatment with an ACE inhibitor or ARB and β-blocker. Eligible patients were hospitalized for a cardiovascular reason within 6 months of study entry or had a plasma BNP of at least 250 pg/mL (72 pmol/L) or an N-terminal proBNP of at least 500 pg/mL (59 pmol/L) in men and 750 pg/mL (89 pmol/L) in women. The trial was stopped prematurely after a median followup of 21 months because of a significant benefit with eplerenone. Eplerenone treatment reduced the primary end point of cardiovascular death or HF hospitalization by 37%, all-cause and cardiovascular mortality by 24%, and hospitalization for HF by 42%. A post hoc analysis of the data also showed a reduction in the incidence of new-onset atrial fibrillation or flutter with eplerenone. The rate of serum potassium greater than 5.5 mEq/L (5.5 mmol/L) was 11.8% in the eplerenone group and 7.2% with placebo.
Current guidelines recommend adding a low-dose aldosterone antagonist to standard therapy to improve symptoms, reduce the risk of HF hospitalization, and increase survival in select patients provided that potassium and renal function can be carefully monitored.1 Based on the clinical trial data low-dose aldosterone antagonists are appropriate for two groups of patients: those with mild to moderately severe SHF (NYHA class II to IV) who are receiving standard therapy and those with left ventricular dysfunction and either acute HF or diabetes early after MI.1,98 An aldosterone antagonist may be preferred over an ARB in patients with persisting symptoms despite ACE inhibitor and β-blocker therapy provided that serum potassium and renal function are acceptable.98 For patients who fall outside the populations studied in these clinical trials, there are no clear guidelines on aldosterone antagonist use. Trials to address the efficacy of aldosterone antagonism in patients with preserved left ventricular systolic function are ongoing.
Despite the clear benefits of aldosterone antagonists in patients with mild to severe SHF, registry data show that only one third of patients meeting guideline criteria for an aldosterone antagonist actually receive one.100 The low use of aldosterone antagonists is likely due in large part to safety concerns. The clinical trial data suggest that aldosterone antagonists in HF are associated with minimal risk when used appropriately (e.g., in those with adequate renal function and with close laboratory monitoring). However, shortly after publication of RALES, an observational study of approximately 1.3 million elderly patients in the Ontario Drug Benefit Program found that the increase in the spironolactone prescription rate following the publication of RALES was accompanied by nearly threefold increases in the rate of hospital admissions and the rate of death related to hyperkalemia.101 In addition, small case series showed that 25% to 35% of patients treated outside the controlled clinical trial setting developed hyperkalemia (>5 mEq/L [>5 mmol/L]) and that 10% to 12% developed serious hyperkalemia.102,103
Potential factors contributing to the high incidence of hyperkalemia in clinical practice include the initiation of aldosterone antagonists in patients with impaired renal function or high potassium concentrations and the failure to decrease or stop potassium supplements when starting aldosterone antagonists. Other risk factors for hyperkalemia include diabetes, inadequate laboratory monitoring, and concomitant use of both ACE inhibitors and ARBs or NSAIDs. The ACC/AHA recently recommended strategies to minimize the risk for hyperkalemia with aldosterone antagonists in HF.1 These strategies are summarized in Table 4-10. Chief among these recommendations is to avoid aldosterone antagonists in patients with renal dysfunction or elevated serum potassium. It is important to emphasize here that serum creatinine may overestimate renal function in the elderly and in patients with decreased muscle mass, in whom creatinine clearance should serve as a guide for the appropriateness of aldosterone antagonist therapy. The risk for hyperkalemia is dose dependent, and the morbidity and mortality reductions with aldosterone antagonists in clinical trials occurred at low doses (i.e., spironolactone 25 mg/day and eplerenone 50 mg/day). Therefore, the doses of aldosterone antagonists should be limited to those associated with beneficial effects in order to decrease the risk for hyperkalemia. Spironolactone also interacts with androgen and progesterone receptors, which may lead to gynecomastia, impotence, and menstrual irregularities in some patients. Such adverse effects are less frequent with eplerenone owing to its low affinity for the progesterone and androgen receptors.
TABLE 4-10 Recommended Strategies for Reducing the Risk for Hyperkalemia with Aldosterone Antagonists
Only 10% of RALES participants were taking β-blockers at baseline since the benefits of β-blockers in HF were not appreciated fully at the time the trial began.20 β-Blockers inhibit plasma renin release and may provide additional suppression of the RAAS when used with ACE inhibitors. Thus, there has been some speculation about whether spironolactone will provide further benefit in patients receiving both ACE inhibitors and β-blockers. However, data from EPHESUS and EMPHASIS provide some clarity to this issue, since the majority of EPHESUS participants were on β-blockers at baseline, and the trial still demonstrated significant reductions in mortality with the addition of eplerenone.21,22
Digoxin In 1785, William Withering was the first to report extensively on the use of foxglove or Digitalis purpurea for the treatment of dropsy (i.e., edema). Although digitalis glycosides have been in clinical use for more than 200 years, not until the 1920s were they clearly demonstrated to have a positive inotropic effect on the heart. Furthermore, it was not until the late 1980s that clinical trials were conducted to critically evaluate the role of digoxin in the therapy of chronic HF. The view of digoxin has also shifted over the past decade. While it was historically considered useful in HF because of its positive inotropic effects, it now seems clear that its real benefits in HF are related to its neurohormonal modulating activity.104,105
The efficacy of digoxin in patients with SHF and supraventricular tachyarrhythmias such as atrial fibrillation is well established and widely accepted. Its role in HF patients with normal sinus rhythm has been considerably more controversial. Clinical trials have also shown that digoxin improves cardiac function, quality of life, exercise tolerance, and HF symptoms in patients with SHF and normal sinus rhythm.106–108 However, these studies involved small numbers of patients followed for short time periods. Although these trials demonstrated hemodynamic and symptomatic improvement in HF patients receiving digoxin, an unresolved issue was the unknown effect of digoxin on mortality. This was of particular concern given the increased mortality seen with other positive inotropic drugs, and finally led to the Digitalis Investigation Group (DIG) trial to determine the effects of digoxin on survival in patients with HF in sinus rhythm.109
The DIG trial was a double-blind, randomized, placebo-controlled trial with the primary end point of all-cause mortality.109 Patients (n = 6,800) with HF symptoms and a LVEF of 45% or less were eligible for the main DIG trial and were randomized to receive digoxin or placebo for a mean followup period of 37 months. Most patients received background therapy with diuretics and ACE inhibitors. Digoxin serum concentrations of 0.5 to 2 ng/mL (0.6 to 2.6 nmol/L) were targeted, with a mean serum digoxin concentration (SDC) of 0.8 ng/mL (1 nmol/L) achieved at 12 months. No significant differences in all-cause mortality were found between patients receiving digoxin and placebo. A trend toward lower mortality due to worsening HF was observed in the digoxin group, although this was offset by a trend toward an increased mortality from other cardiovascular causes (presumably arrhythmias) in patients receiving digoxin. Importantly, digoxin reduced hospitalizations for worsening HF by 28% compared with placebo (P <0.001). Therefore, DIG is the first trial to show that a positive inotropic agent does not increase mortality and actually decreases morbidity in patients with SHF. On the other hand, among an additional 988 patients with a LVEF greater than 45% (diastolic dysfunction) who were enrolled in an ancillary DIG trial, there was no apparent benefit of digoxin on hospitalizations or mortality during the 37-month followup period.110
The PROVED and RADIANCE trials investigated the effect of digoxin withdrawal in patients with chronic HF and normal sinus rhythm and further defined the role of digoxin in this setting.107,108 Both of these trials were short-term (12-week), prospective, randomized, and placebo-controlled and were conducted prior to the use of β-blockers. Together, data from these trials suggested that digoxin produces important symptomatic benefits and that digoxin withdrawal results in worsening HF, decreased exercise capacity, and a reduction in ejection fraction. A post hoc analysis of the DIG trial data supports findings that discontinuation of digoxin may be detrimental. Specifically, among patients treated with digoxin prior to enrollment in the DIG trial, those assigned to the placebo arm (i.e., those discontinuing digoxin therapy) had an increased risk of all-cause hospitalization and HF-related hospitalization compared with patients assigned to the digoxin arm (i.e., those continuing digoxin therapy).111
Retrospective analyses of the combined PROVED/RADIANCE database112 and the DIG trial database113 suggest that the clinical benefits of digoxin are achieved at lower SDCs, with no additional benefit with higher concentrations. In particular, analysis of digoxin-treated patients in the PROVED and RADIANCE trials showed similar clinical outcomes among those with a SDC between 0.5 and 0.9 ng/mL (between 0.6 and 1.2 nmol/L) as those with higher serum concentrations.112 While the DIG trial showed no reduction in mortality in the study population overall, a comprehensive analysis of the DIG trial database found that lower SDCs were associated with decreased mortality, whereas higher concentrations were not.113 Specifically, compared with placebo, SDCs of 0.5 to 0.9 ng/mL (0.6 to 1.2 nmol/L) 1 month after digoxin initiation were associated with lower mortality, all-cause hospitalizations, and HF hospitalizations. Serum concentrations greater than or equal to 1 ng/mL (1.3 nmol/L) were associated with lower HF hospitalizations with no effect on mortality. A digoxin dose of 0.125 mg daily or less was predictive of SDCs of 0.4 to 0.9 ng/mL (0.5 to 1.2 nmol/L). While an initial, well-publicized study suggested that digoxin might be harmful in women,114 subsequent analyses show no increased risks with digoxin in women, particularly with SDCs less than 1 ng/mL (1.3 nmol/L).113,115
Based on the available data, for most patients, the target SDC should be 0.5 to 1 ng/mL (0.6 to 1.3 nmol/L). This more conservative target would also be expected to decrease the risk of adverse effects from digoxin toxicity. In fact, recent assessment of the rate of digoxin toxicity has suggested a significant decline in the overall incidence.116 In most patients with normal renal function, this serum concentration range can be achieved with a daily dose of 0.125 mg. Patients with decreased renal function, the elderly, or those receiving interacting drugs (e.g., amiodarone) should receive 0.125 mg daily or every other day. Routine measuring of SDCs is not necessary in the absence of suspected digoxin toxicity, worsening renal function, institution of an interacting drug, or other conditions that may significantly affect SDC. In patients with atrial fibrillation and a rapid ventricular response, the historic practice of increasing digoxin doses (and concentrations) until rate control is achieved is no longer recommended. Digoxin alone is often ineffective to control ventricular response in patients with atrial fibrillation and increasing the dose only increases the risk of toxicity. Digoxin combined with a β-blocker or amiodarone is superior to either agent alone for controlling ventricular response in patients with atrial fibrillation and HF.1 Therefore, target SDCs are the same regardless of whether the patient is in sinus rhythm or atrial fibrillation. Several equations and nomograms have been proposed to estimate digoxin maintenance doses based on estimated renal function for a particular patient and population pharmacokinetic parameters. These methods are extensively reviewed elsewhere.117 More recently, based on post hoc analyses from the DIG, PROVED, and RADIANCE trials, investigators developed a digoxin dosing nomogram that targets a lower digoxin plasma concentration.118 In the absence of supraventricular tachyarrhythmias, a loading dose is not indicated because digoxin is a mild inotropic agent that will produce gradual effects over several hours, even after loading.
The DIG trial was conducted prior to the proven benefits and widespread use of β-blockers in HF, and, thus, some have called for a reexamination of digoxin in the context of contemporary HF therapy.119Based on the available data, digoxin’s place in the pharmacotherapy of chronic SHF can be summarized for two patient groups. In patients with HF and supraventricular tachyarrhythmias such as atrial fibrillation, it should be considered early in therapy to help control ventricular response rate. For patients in normal sinus rhythm, although digoxin does not improve survival, its effects on symptom reduction and clinical outcomes are evident in patients with mild to severe HF with reduced systolic function. And thus, it should be used in conjunction with other standard HF therapies including diuretics, ACE inhibitors, and β-blockers in patients with symptomatic HF to reduce hospitalizations.1,27 In the absence of digoxin toxicity or serious adverse effects, digoxin should be continued in most patients. Digoxin withdrawal may be considered for asymptomatic patients who have significant improvement in systolic function with optimal ACE inhibitor and β-blocker treatment.120
Nitrates and Hydralazine Nitrates and hydralazine were originally combined in the treatment of SHF because of their complementary hemodynamic actions. Nitrates, by serving as nitric oxide donors, activate guanylate cyclase to increase cyclic guanosine monophosphate (cGMP) in vascular smooth muscle resulting in venodilation and decreased preload. Hydralazine is a direct-acting arterial vasodilator causing a decrease in SVR and resultant increases in SV and CO (see Fig. 4-1). However, recent evidence suggests that the beneficial effects of hydralazine and nitrates extend beyond their hemodynamic actions and interfere with the biochemical processes driving HF progression.121
The efficacy of the combination of hydralazine and ISDN has been evaluated in three large, randomized clinical trials. The first trial predated the use of ACE inhibitors and β-blockers and found that the combination of hydralazine 75 mg and ISDN 40 mg, each given four times daily, reduced mortality compared with placebo in patients receiving diuretics and digoxin.122 A subsequent trial comparing the combination with an ACE inhibitor demonstrated greater mortality reduction with the ACE inhibitor.123 Post hoc analysis of these trials suggested that the combination of hydralazine and ISDN was particularly effective in African Americans, and led to examining the efficacy of adding the combination to standard therapy in this group.121
The African-American Heart Failure Trial (A-HeFT) randomized 1,050 self-identified African Americans with NYHA class III or IV SHF receiving standard therapy to hydralazine plus ISDN or placebo.124The trial used a fixed-dose combination product, BiDil®, which contains hydralazine 37.5 mg and ISDN 20 mg. Therapy was initiated as a single tablet given three times daily, and then titrated to two tablets three times daily if tolerated. The trial was terminated early because of a significant 43% reduction in all-cause mortality in patients receiving hydralazine/ISDN compared with placebo. The primary composite end point of mortality, hospitalizations for HF, and quality of life was also significantly improved with the combination product. Based on these results, BiDil® was approved by the FDA to treat HF exclusively in African Americans.
The mechanism for the beneficial effects of hydralazine/ISDN remains uncertain but is most likely related to normalization of the increased oxidative stress and reduced nitric oxide signaling that contributes to HF progression. By serving as a nitric oxide donor, nitrates increase nitric oxide bioavailability and hydralazine reduces oxidative stress.121,123 Nitric oxide attenuates myocardial remodeling and may play a protective role in HF. African Americans may have less nitric oxide availability compared with non–African Americans, and, thus, may derive particular benefit from therapy that enhances nitric oxide bioavailability. Whether the benefits of adding hydralazine/ISDN to standard therapy extend to non–African Americans remains to be prospectively evaluated.
Guidelines recommend the addition of hydralazine and nitrates to self-described African Americans with SHF and moderate to severe symptoms despite therapy with ACE inhibitors, diuretics, and β-blockers.1,27 This combination is also reasonable to consider in all patients who continue to have symptoms despite optimized therapy with an ACE inhibitor (or ARB) and β-blocker.1,27 For patients unable to tolerate an ACE inhibitor because of cough, an ARB is recommended as the first-line alternative.1 Hydralazine and a nitrate might be reasonable in patients unable to tolerate either an ACE inhibitor or ARB because of renal insufficiency, hyperkalemia, or possibly hypotension.1
Despite the demonstrated benefits from hydralazine/ISDN, this therapy is significantly underused.121 There are several potential obstacles that may explain this low rate of use. The first is the need for frequent dosing, with the fixed-dose combination administered three times daily. Second, adverse effects are common with hydralazine/ISDN, with nearly 30% of patients reporting dizziness, as well as headache and GI distress occurring more frequently with this combination compared with placebo in clinical trials.122,124 A third potential obstacle is the high cost of the BiDil® fixed-dose combination product compared with that of the individual generic drugs purchased separately. Because of the high cost, many clinicians use generic hydralazine and ISDN as separate agents, rather than the combination product. Although the generic and brand name products are not bioequivalent as determined in healthy volunteer studies, it is unknown if these pharmacokinetic differences impact clinical outcomes.121
Calcium Channel Blockers 
Calcium channel blockers can provide symptom-targeted treatment in patients with HFpEF by decreasing HR and increasing exercise tolerance. They can also provide disease-targeted therapy by treating HTN and coronary artery disease. However, the beneficial effect of these agents on exercise tolerance is not always paralleled by improved LV diastolic function or increased relaxation rate. Nonetheless, a number of small clinical trials have shown that the use of these agents results in both short- and long-term improvement in exercise capacity in patients with HFpEF.27
Of the calcium channel blockers, the nondihydropyridines (verapamil and diltiazem) are the most effective because they lower HR in addition to lowering BP.125 Sustained-release nifedipine, because of its strong vasodilator properties, tends to cause hypotension, reflex tachycardia, and peripheral edema. These characteristics make it less useful in HFpEF. Amlodipine may be effective because it reduces BP. Initial doses are verapamil 120 to 240 mg/day, diltiazem 90 to 120 mg/day, and amlodipine 2.5 mg/day.
Heart block is a contraindication for the nondihydropyridines. The most common adverse effects are bradycardia and heart block (for the nondihydropyridines). Peripheral edema and headache also are common. Nondihydropyridines exacerbate the bradycardic effects of β-blockers, and verapamil raises digoxin serum concentrations by 70%. Diltiazem increases cyclosporine, tacrolimus, and sirolimus serum concentrations. Generic formulations, but not necessarily generic equivalents to the original brand names, are available for some of the calcium channel blockers.
Treatment of Concomitant Disorders
HF is often accompanied by other disorders whose natural history or therapy may affect morbidity, mortality, and treatment approach. Optimal management of these concomitant disorders in the context of the patient’s HF is an important consideration in the overall care of the patient.
Hypertension Although ischemic heart disease has replaced HTN as the most common cause of HF, still nearly two thirds of patients with HF have current or a previous history of HTN.1 HTN can contribute directly to the development of both SHF and HFpEF as well as indirectly by increasing the risk of coronary artery disease. Effective treatment of HTN reduces the risk of developing HF, especially in patients with diabetes.1 Pharmacotherapy of HTN in patients with SHF should initially involve agents that can treat both disorders such as ACE inhibitors, β-blockers, and diuretics. Target levels of BP should be consistent with current guidelines.1,27,48 If control of HTN is not achieved after optimizing treatment with these agents, the addition of an ARB, aldosterone antagonist, ISDN/hydralazine, or a second-generation calcium channel blocker such as amlodipine (or possibly felodipine) should be considered. Medications that should be avoided in patients with SHF include the calcium channel blockers with negative inotropic effects (e.g., verapamil, diltiazem) and direct-acting vasodilators (e.g., minoxidil) that cause sodium retention.
In patients with HFpEF, both verapamil and diltiazem can be safely used. However, clinicians should remember that HFpEF is associated with HTN and aging, making it a common diagnosis in elderly women. Because these women often are frail and have low muscle mass, their creatinine clearance and renal function may be compromised. Special care must be taken when selecting and titrating doses of drugs such as diuretics, ACE inhibitors, and ARBs and close attention paid to monitoring serum creatinine and electrolytes.
Angina Coronary artery disease is the most common etiology of SHF. Appropriate management of coronary disease and its risk factors is thus an important strategy for the prevention and treatment of HF. Coronary revascularization should be strongly considered in patients with both HF and angina.1 Pharmacotherapy of angina in patients with HF should utilize drugs that can successfully treat both disorders. Nitrates and β-blockers are effective antianginals and are the preferred agents for patients with both disorders since they may improve hemodynamics and clinical outcomes.1 It should be noted that the antianginal effectiveness of these agents may be significantly limited if fluid retention is not controlled with diuretics. Similar to their use in HTN, both amlodipine and felodipine appear to be safe to use in this setting. Optimization of other treatments for secondary prevention of coronary and other atherosclerotic vascular disease should also be considered.48 Two large trials found that despite significant reductions in LDL cholesterol, rosuvastatin did not improve outcomes including mortality, nonfatal MI, nonfatal stroke, or hospital admission for cardiovascular causes in patients with SHF.126,127 Therefore, the current data do not support the routine use of statins in SHF, although the precise role of these agents remains controversial.
Atrial Fibrillation Atrial fibrillation is the most frequently encountered arrhythmia and it is commonly found in patients with HF, affecting 10% to 50% of patients with the prevalence increasing in parallel to the severity of HF.30The high incidence of atrial fibrillation in these patients is not surprising since each disorder predisposes to the other and they share many risk factors including coronary artery disease, diabetes, obesity, and HTN. The presence of atrial fibrillation in patients with HF is associated with a worse long-term prognosis.1,30 Detrimental effects of these disorders include increased risk of thromboembolism secondary to stasis of blood in the atria, a reduction in CO due to loss of the atrial contribution to ventricular filling, and hemodynamic compromise from the rapid ventricular response.30Moreover, HF exacerbations and atrial fibrillation are closely linked and it is often difficult to determine which disorder caused the other. For example, worsening HF results in volume overload, which, in turn, causes atrial distension and increases the risk of atrial fibrillation. Similarly, atrial fibrillation with a rapid ventricular response can reduce CO and lead to HF exacerbation. Thus, optimal management according to established guidelines is required with careful attention paid to control of ventricular response and anticoagulation for stroke prevention (see Chap. 8).128
Digoxin is frequently used to slow ventricular response in patients with HF and atrial fibrillation. However, it is more effective at rest than with exercise and it does not affect the progression of HF. β-Blockers are more effective than digoxin and have the added benefits of improving morbidity and mortality in patients with SHF. Combination therapy with digoxin and a β-blocker may be more effective for rate control than either agent used alone. Calcium channel blockers with negative inotropic effects such as verapamil or diltiazem should be avoided. Amiodarone is a reasonable alternative for rate control in those patients not responding to digoxin and/or β-blockers or with contraindications to these agents.128 Appropriate selection of antithrombotic therapy for stroke prevention that takes into consideration the presence of risk factors for thromboembolism in an individual patient is also required.126,128
Because of the close association between atrial fibrillation, HF exacerbations, and hospitalizations, restoration and maintenance of sinus rhythm (i.e., rhythm control) is often attempted instead of the rate control approach. Although initial trials such as AFFIRM showed no differences in outcomes between the rhythm and rate control approaches, less than 10% of the patients in this study had left ventricular dysfunction.129 The Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial prospectively compared the rhythm and rate control approaches in nearly 1,400 patients with symptomatic HF and LVEF ≤35%.130 Rhythm control was primarily achieved with amiodarone, whereas a β-blocker and digoxin were used for rate control. Compared with rate control, there were no improvements in mortality, stroke, death from cardiovascular causes, or HF hospitalizations in the rhythm control arm. Therefore, overall rhythm control appears to offer no specific advantages over rate control in this population and can be reserved for patients in whom the rate cannot be controlled or who remain symptomatic. In general, amiodarone is the preferred agent if the rhythm control approach is taken. Although it has many noncardiac toxicities, amiodarone does not have cardiodepressant or significant proarrhythmic effects and appears to be safe in HF. Dofetilide also appears to be safe and effective in this population.30,128 Class I antiarrhythmics should be avoided.30,128
Diabetes Diabetes is a common comorbid condition in patients with HF, with current estimates indicating it is present in approximately one third of HF patients.131 As an important risk factor for coronary artery disease, diabetes directly contributes to the development of HF. Importantly though, diabetes is also a risk factor for HF, particularly in women, independent of coronary artery disease or HTN.131Diabetes is associated with more rapid HF progression and is a significant predictor of mortality in patients with HF.131
Pharmacotherapy of diabetes in patients with HF should be targeted to control hyperglycemia according to current guidelines, although this approach is not proven to reduce the risk of HF development.1 The optimal approach to the treatment of diabetes in this population remains uncertain as most clinical trials of diabetes medications excluded patients with moderate to severe HF. Some medications used to treat diabetes can have important adverse effects in patients with HF. Because the TZDs (pioglitazone and rosiglitazone) are associated with fluid retention, these medications should not be used in patients with NYHA class III or IV HF and used cautiously in patients with NYHA class I or II symptoms with close observation needed to detect weight gain, edema formation, or HF exacerbation. TZDs should be discontinued in patients developing symptoms related to volume overload. Use of metformin in patients with HF has been contraindicated because of the purported risk of lactic acidosis. However, the product labeling was recently revised removing this contraindication, although a warning still remains specifically in patients with hypoperfusion and hypoxemia. A growing number of observational reports demonstrate that not only is metformin safe in HF, but it is also associated with improved morbidity and mortality.132,133 However, no prospective data on metformin’s safety and efficacy in HF are available, so careful monitoring of volume status and renal function is needed when this medication is used in these patients.131
Drug Class Information
Diuretics Loop diuretics, as described earlier, represent the typical diuretic therapy for patients with HF due to their potency and, as such, are the only diuretics discussed here.55,60 There are currently three loop diuretics available that are used routinely: furosemide, bumetanide, and torsemide. They share many similarities in their pharmacodynamics, with their differences being largely pharmacokinetic in nature. Relevant information on the loop diuretics is shown in Tables 4-8 and 4-9. Following oral administration, the peak effect with all the agents occurs in 30 to 90 minutes, with duration of 2 to 3 hours (slightly longer for torsemide). Following IV administration, the diuretic effect begins within minutes. All three drugs are highly (>95%) bound to serum albumin and enter the nephron by active secretion in the proximal tubule. The magnitude of effect is determined by the peak concentration achieved in the nephron, and there is a threshold concentration that must be achieved before any diuresis is seen.
The biggest difference between the agents is bioavailability. Bioavailability of bumetanide and torsemide is essentially complete (80% to 100%), whereas furosemide bioavailability exhibits marked intrapatient and interpatient variability. Furosemide bioavailability ranges from 10% to 100%, with an average of 50%. Thus, if bioequivalent IV and oral doses are desired, oral furosemide doses should be approximately double that of the IV dose, whereas IV and oral doses are the same for torsemide and bumetanide. Coadministration of furosemide and bumetanide with food can decrease bioavailability significantly, whereas food has no effect on bioavailability of torsemide. The intraabdominal congestion that can occur in HF also may slow the rate (and thus decrease the peak concentration) of furosemide, which can reduce the diuretic’s efficacy. Thus, furosemide is most problematic with respect to rate and extent of absorption and the factors that influence it, whereas torsemide has the least variable bioavailability.
Recent data suggest that these differences in bioavailability and variability may have clinical implications. For example, several studies have suggested that torsemide is absorbed reliably and is associated with better outcomes than the more variably absorbed furosemide.134,135 Torsemide is preferred in patients with persistent fluid retention despite high doses of other loop diuretics. And while the costs of torsemide exceed those of furosemide, pharmacoeconomic analyses suggest that the costs of care are similar or less with torsemide.135 These data require confirmation in controlled, double-blind clinical trials but provide preliminary evidence that the more reliably absorbed loop diuretics may be superior to furosemide.
HF is one of the disease states in which the maximal response to loop diuretics is reduced. This is believed to result from a decrease in the rate of diuretic absorption and/or increased proximal or distal tubule reabsorption of sodium, possibly due to increased activity of the Na–K–2Cl transporter.61 As a consequence, loop diuretics exhibit a ceiling effect in HF, meaning that once the ceiling dose is reached, no additional diuretic response is achieved by increasing the dose. Thus, when this dose is reached, additional diuresis can be achieved by giving the drug more often (twice daily or occasionally three times daily) or by giving combination diuretic therapy. Multiple daily dosing achieves a more sustained diuresis throughout the day. When dosed two or three times daily, the first dose is usually given first thing in the morning and the final dose in late afternoon/early evening. The appropriate chronic dose of a loop diuretic is that which maintains the patient at a stable dry weight without symptoms of dyspnea. Ranges of doses of loop diuretics and recommended ceiling doses are shown in Table 4-8.
Diuretics cause a variety of metabolic abnormalities, with severity related to the potency of the diuretic. The reader is referred to Chapter 3 for a detailed discussion on the adverse effects of diuretic therapy. Hypokalemia is the most common metabolic disturbance with thiazide and loop diuretics, which in HF patients may be exacerbated by hyperaldosteronism. Hypokalemia increases the risk for ventricular arrhythmias in HF and is especially worrisome in patients receiving digoxin. It is often accompanied by hypomagnesemia. Since adequate magnesium is necessary for entry of potassium into the cell, co-supplementation with both magnesium and potassium may be necessary to correct the hypokalemia. Concomitant ACE inhibitor (or ARB) and/or aldosterone antagonist therapy may help to minimize diuretic-induced hypokalemia because these drugs tend to increase serum potassium concentration through their inhibitory effect on aldosterone secretion. Nonetheless, the serum potassium concentration should be monitored closely in HF patients and supplemented appropriately when needed. In addition to metabolic abnormalities, a recent post hoc analysis of the DIG trial suggested that chronic diuretic use was associated with increased risk of mortality and hospitalization.136 These findings must be interpreted with caution because this trial was not designed to evaluate outcomes associated with diuretic therapy. However, they do serve to remind clinicians of the importance of appropriate patient selection and monitoring when using diuretic therapy.
ACE Inhibitors A number of ACE inhibitors are currently available; those commonly used in the treatment of patients with HF are summarized in Table 4-8. Although ACE inhibitors vary in their chemical structure (e.g., sulfhydryl vs. non–sulfhydryl-containing agents) and tissue affinity, the major differences in the ACE inhibitors are not in these pharmacologic properties but in their pharmacokinetic properties.16 To date all ACE inhibitors studied improve symptoms and mortality in SHF.16 However, it seems most prudent to use those agents documented to reduce morbidity and mortality because the dose required for these end points has been determined.1
To minimize the risk of hypotension and renal insufficiency, ACE inhibitor therapy should be started with low doses followed by gradual titration as tolerated to the target doses.1 Asymptomatic hypotension should not be considered a contraindication to starting therapy with an ACE inhibitor, although initiation or dose increases in patients with systolic BPs less than 90 to 100 mm Hg should be done cautiously. Renal function and serum potassium should be evaluated at baseline and within 1 to 2 weeks after therapy is started with subsequent periodic assessments. In the outpatient setting, clinicians should wait at least 2 weeks between dose increases and renal function and potassium should be checked 1 to 2 weeks after each increase. After titration of the drug to the target dose, most patients tolerate chronic therapy with few complications. Although symptoms may improve within a few days of initiating therapy, it may take weeks to months before the full benefits are apparent. Even if symptoms do not improve, long-term ACE inhibitor therapy should be continued to reduce the risk of mortality and hospitalization. Careful attention to appropriate doses of diuretics is important since fluid overload may blunt the beneficial effects of ACE inhibitors and overdiuresis increases the risk of hypotension and renal insufficiency.
Since ACE inhibitors were the first agents to show improvements in survival and were frequently used as background therapy in clinical trials of other medications, they are often used as the initial therapy in patients with HF. Traditionally, after titration of the ACE inhibitor dose, the addition of β-blockers was then considered. As a result, the expected ACE inhibitor–mediated decrease in BP prevented some clinicians from starting β-blocker therapy. However, initiation of β-blocker therapy should not be delayed while the ACE inhibitor is titrated to the target dose since low–intermediate ACE inhibitor doses are equally effective as higher doses for improving symptoms and survival.1,70 Also, in β-blocker clinical trials, most patients were receiving background therapy with low–intermediate ACE inhibitor doses. Thus, in most patients, ACE inhibitors should be the initial therapy but it is important to remember that even a small dose of ACE inhibitor is better than no ACE inhibitor and that the greatest benefit is seen when these agents are combined with a β-blocker.
Because of the high prevalence of coronary artery disease in patients with HF, aspirin is frequently coadministered with ACE inhibitors. Whether aspirin may attenuate the hemodynamic and mortality benefits of ACE inhibitors remains controversial. The postulated mechanism of this interaction involves opposing effects on synthesis of vasodilatory prostaglandins. The ACE inhibitor–mediated increase in bradykinin increases the synthesis of vasodilatory prostaglandins that have favorable hemodynamic benefits in HF. Because of aspirin’s effect on prostaglandin synthesis, this potentially beneficial action of ACE inhibitors may be attenuated. However, in contrast with studies that showed an ACE inhibitor–aspirin interaction, other investigators have found no interaction, even in patients without coronary artery disease or with impaired renal function.137 It is currently recommended that the decision to use each of these medications be made based on whether an individual patient has indications for each drug.1,27Aspirin doses of 160 mg/day or less should be considered. In the absence of atherosclerotic vascular disease, aspirin therapy is not recommended.27
Adverse Effects The primary adverse effects of ACE inhibitors are secondary to their major pharmacologic effects of suppressing angiotensin II and increasing bradykinin. The most common adverse effects with these agents are hypotension and functional renal insufficiency resulting from the drug-related reductions in angiotensin II. ACE inhibitors reduce BP in nearly all patients, with hypotension becoming problematic when symptoms such as dizziness, light-headedness, blurred vision, presyncope, or syncope are observed. Hypotension occurs most frequently soon after therapy is started or after an increase in dose, although it may occur at any time during treatment. Risk factors for hypotension include hyponatremia (serum sodium <130 mEq/L [<130 mmol/L]), hypovolemia, and overdiuresis.1 The risk of hypotension may be minimized by initiating therapy with lower ACE inhibitor doses and/or temporarily withholding or reducing the dose of diuretic, and liberalizing salt and fluid intake.1 An often overlooked solution to hypotension is to space the administration times of vasoactive medications (e.g., diuretics and β-blockers) throughout the day so that these medications are not all administered at or near the same time. Also, if the patient is receiving other vasodilating drugs (e.g., nitrates, amlodipine), the need for these medications or at least the feasibility of dose reduction should be considered. Many patients who experience symptomatic hypotension early in therapy are still good candidates for long-term treatment if risk factors for low BP are addressed.
Functional renal insufficiency causes increases in serum creatinine and blood urea nitrogen (BUN). As CO and renal blood flow decline, renal perfusion is maintained by the vasoconstrictor effect of angiotensin II on the efferent arteriole. Patients most dependent on this system for maintenance of renal perfusion (and therefore most likely to develop functional renal insufficiency with ACE inhibitors) are those with severe HF, hypotension, hyponatremia, volume depletion, bilateral renal artery stenosis, and concomitant use of NSAIDs.138 Sodium depletion, usually secondary to diuretic therapy, is the most important factor in the development of functional renal insufficiency with ACE inhibitor therapy. Renal insufficiency therefore can be minimized in many cases by reduction in diuretic dosage or liberalization of sodium intake. Increases in serum creatinine of 10% to 20% from baseline are commonly observed after initiation of ACE inhibitor therapy. In some patients, the serum creatinine will return to baseline levels without a reduction in ACE inhibitor dose.138 Increases in serum creatinine of >0.5 mg/dL if the baseline creatinine is <2 mg/dL or of >1 mg/dL if the creatinine is >2 mg/dL should prompt clinicians to reduce the dose of ACE inhibitors or reconsider ACE therapy and evaluate potential causes for the abrupt decline in renal function.138The safety and efficacy of ACE inhibitors in patients with baseline serum creatinine >2.5 mg/dL (>221 μmol/L) is uncertain as these patients were usually excluded from clinical trials. Caution should also be exercised when using ACE inhibitors in such patients. Since renal dysfunction with ACE inhibitors is secondary to alterations in renal hemodynamics, it is almost always reversible on discontinuation of the drug.138
Careful dose titration can minimize the risks of hypotension and transient worsening of renal function. Thus, usual initial doses should be about one fourth the final target dose with slow upward dose titration based on BP and serum creatinine. In certain patients, especially those hospitalized patients who seem at high risk for hypotension or worsening of renal function, it also may be advisable to initiate therapy with a short-acting agent such as captopril. This will help minimize the duration of these adverse effects should they occur. Once stabilized on captopril, the patient can then be switched to an agent given once daily.
Hyperkalemia with ACE inhibitor therapy can occur and is due to the reduced feedback of angiotensin II to stimulate aldosterone release. Hyperkalemia is most likely to occur in patients with renal insufficiency and in those taking concomitant potassium supplements, potassium-containing salt substitutes, or potassium-sparing diuretic therapy (including an aldosterone antagonist), especially if they have diabetes.138 The more widespread use of aldosterone antagonists (e.g., spironolactone) in patients with HF may increase the risk of hyperkalemia.101
ACE inhibitors are also associated with other important adverse effects. A dry, hacking cough is the most common reason for discontinuation of ACE inhibitors, and this adverse effect occurs with a similar frequency with all the agents.1 The incidence of cough is reported to range from 5% to 10%, but a recent report suggests cough occurs significantly more often (up to 15% of patients) than what is reported in the product labeling.139 The cough is usually nonproductive, occurs within the first few months of therapy, resolves within 1 to 2 weeks of drug discontinuation, and reappears with rechallenge. Cough occurs in up to 40% of patients with HF, independent of ACE inhibitor use; therefore, it is important to rule out other potential causes of cough, such as pulmonary congestion. Because cough is a bradykinin-mediated effect, replacement of ACE inhibitor therapy with an ARB would be reasonable in those patients who cannot tolerate the cough. Angioedema is a rare, occurring in less than 1% of patients receiving an ACE inhibitor, but potentially life-threatening complication that may also be due to bradykinin accumulation. It occurs more frequently in African Americans, women, and patients with HF than in other populations.140,141 Approximately 50% of patients develop angioedema within the first 90 days of therapy, but it can occur years after treatment was started.140 Use of ACE inhibitors is contraindicated in patients with a history of angioedema. Extreme caution should be exercised if ARBs are used as an alternative therapy in patients with ACE inhibitor–induced angioedema, as cross-reactivity is reported.1,91,141 ACE inhibitors are contraindicated during the second and third trimesters of pregnancy due to the increased risk of fetal renal failure, intrauterine growth retardation, and other congenital defects. A recent analysis using a Medicaid database of nearly 30,000 patients suggests that first-trimester use of ACE inhibitors should also be avoided as the risk of major congenital defects was increased 2.7-fold in infants exposed to these agents during the first trimester.142
Angiotensin II Receptor Blockers Although ACE inhibitors remain the agents of first choice to treat Stage C SHF, ARBs are now the recommended alternatives in patients who are unable to tolerate an ACE inhibitor.1Although numerous ARBs are currently available, only three agents, candesartan, valsartan, and losartan, are recommended in the treatment guidelines.1,27 The efficacy of these agents is supported by clinical trial data that document a target dose associated with improved survival and other important outcomes in patients with decreased LVEF.87–89,91,92 ARBs are also alternatives to ACE inhibitors in patients with Stage A or B HF.1
The clinical use of ARBs is also similar to that of ACE inhibitors. Therapy should be initiated at low doses and then titrated to target doses (Table 4-8).1 BP, renal function, and serum potassium should be evaluated within 1 to 2 weeks after initiation of therapy and after increases in dose and these end points used to guide subsequent dose changes. It is not necessary to reach target doses before adding a β-blocker, although incremental benefits may be associated with higher doses of ARBs.86
Adverse Effects The ARBs have a low incidence of adverse effects. Since they do not affect bradykinin, they are not associated with cough and have a lower risk of angioedema than ACE inhibitors.141However, because of reports of recurrences of angioedema after ARB administration to patients with a history of ACE inhibitor–related angioedema, ARBs should be used with extreme caution in any patient with a history of angioedema as cross-reactivity may occur in 2% to 17% of patients.91,94,143
The major adverse effects are related to suppression of the RAAS. The incidence and risk factors for developing hypotension, decreases in renal function, and hyperkalemia with the ARBs are similar to those with ACE inhibitors.1,137 Thus, ARBs are not alternatives in patients who develop these complications from ACE inhibitors. Careful monitoring is required when an ARB is used with another inhibitor of the RAAS (e.g., ACE inhibitor or aldosterone antagonist) as this combination increases the risk of these adverse effects. Similar to the ACE inhibitors, the ARBs are contraindicated in the second and third trimesters of pregnancy and should be avoided in the first trimester because of increased risk of fetal/neonatal morbidity and mortality. Neither candesartan nor valsartan is metabolized by the cytochrome P450 system, so no pharmacokinetic drug–drug interactions with these agents are expected.
β-Blockers Metoprolol succinate, carvedilol, and bisoprolol are the only β-blockers shown to reduce mortality in large trials in patients with SHF. Metoprolol and bisoprolol selectively block the β1-receptor, while carvedilol blocks the β1-, β2-, and α1-receptors and also possesses antioxidant effects. While there is no clear evidence that these pharmacologic differences result in differences in efficacy among agents, they may aid in selection of a specific agent. For example, carvedilol is expected to have greater antihypertensive effects than the other agents because of its α-receptor blocking properties and may be preferred in patients with poorly controlled BP. Conversely, metoprolol or bisoprolol may be preferred in patients with low BP or dizziness and in patients with significant airway disease. Bisoprolol is eliminated approximately 50% by the kidneys, whereas metoprolol and carvedilol are essentially completely metabolized and undergo extensive hepatic first-pass metabolism.
There is fairly strong evidence that benefits of β-blockers in SHF are not a class effect. Specifically, in a study powered for mortality reduction, there was no difference in survival between the nonselective β-blocker bucindolol and placebo.144 While there has been considerable debate over why bucindolol failed to provide a survival benefit, it may be related to the drug’s ancillary properties or differences among β-blocker trials in the characteristics of study participants. Additional data suggest that bucindolol’s effects on survival might be genotype specific, as described in Personalized Pharmacotherapy below. In the absence of bucindolol’s approval for HF, β-blocker use should be confined to one of the agents with proven survival benefits, especially given the diversity among β-blockers in their receptor sensitivities and ancillary properties.
There has been much debate over whether one β-blocker is superior to another. Specifically, it has been hypothesized that nonselective blockade with carvedilol might produce greater benefits than β1-selective blockade. This hypothesis is based on observations that the β1-receptor is downregulated, and the β2- and α1-receptors account for a larger proportion of total cardiac adrenergic receptors in the failing heart. Only one trial with a mortality end point has provided a head-to-head comparison of carvedilol and a β1-selective blocker. The Carvedilol Or Metoprolol European Trial (COMET) compared carvedilol 25 mg twice daily and immediate-release metoprolol 50 mg twice daily and found a significant 17% lower mortality rate in patients treated with carvedilol.145 However, concerns regarding the formulation and dose of metoprolol used in COMET limit the conclusions that can be drawn from these findings. Specifically, the study used the immediate-release formulation of metoprolol (metoprolol tartrate), not the sustained-release formation (metoprolol succinate) shown to reduce mortality. The efficacy of the immediate-release formulation in reducing mortality in HF has not been proven. Metoprolol succinate provides more consistent plasma concentrations over a 24-hour period and appears to provide more favorable effects on HR variability, autonomic balance, and BP, suggesting that this formulation might be superior to immediate-release metoprolol.146 The target dose of metoprolol also differed between COMET and MERIT-HF. The target dose in COMET was 100 mg/day (50 mg twice daily), whereas the target dose of metoprolol in MERIT-HF was 200 mg/day. Many question whether the degree of β-blockade achieved in COMET with immediate-release metoprolol 50 mg twice daily is comparable to that achieved with metoprolol succinate 200 mg/day in MERIT-HF or carvedilol 25 mg twice daily in COMET. Thus, the debate over β-blocker superiority continues, and while some clinicians would argue superiority of carvedilol, it seems clear that what is most important is that one of the three β-blockers proven to reduce mortality is used.
Adverse Effects Possible adverse effects with β-blocker use in HF include bradycardia or heart block, hypotension, fatigue, impaired glycemic control in diabetic patients, bronchospasm in patients with asthma, and worsening HF. Clinicians should monitor vital signs and carefully assess for signs and symptoms of worsening HF during β-blocker initiation and uptitration. Hypotension is more common with carvedilol due to its α1-receptor blocking properties. Bradycardia and hypotension generally are asymptomatic and require no intervention; however, β-blocker dose reduction is warranted in symptomatic patients. Fatigue usually resolves after several weeks of therapy, but sometimes requires dose reduction. In diabetic patients, β-blockers may worsen glucose tolerance and can mask the tachycardia and tremor (but not sweating) that accompany hypoglycemia. In addition, nonselective agents such as carvedilol may prolong insulin-induced hypoglycemia and slow recovery from a hypoglycemic episode. Despite this, there is evidence that carvedilol produces better glycemic control in diabetic patients compared with immediate-release metoprolol and may improve insulin sensitivity.147 Furthermore, post hoc analysis of HF trials shows that β-blockers are well tolerated and significantly reduce morbidity and mortality in patients with diabetes and SHF.148 Thus, while β-blockers should be used cautiously in patients with recurrent hypoglycemia, concerns of masking symptoms of hypoglycemia or worsening glycemic control should not preclude β-blocker use in patients with diabetes. Patients with diabetes should be warned of these potential adverse effects, and blood glucose monitored with initiation, adjustment, and discontinuation of β-blocker therapy. Adjustment of hypoglycemic therapy may be necessary with concomitant β-blocker use in diabetics.
Uptitration should be avoided if the patient experiences signs of worsening HF, including volume overload and poor perfusion. Fluid overload may be asymptomatic and manifest solely as an increase in body weight. Mild fluid overload may be managed by intensifying diuretic therapy. Once the patient has been stabilized, dose titration may continue as tolerated until the target or highest tolerated dose is reached. Despite their negative inotropic effects, continuing β-blocker therapy during hospitalization for acute decompensated HF appears to neither worsen symptoms nor delay clinical improvement. In fact, β-blocker withdrawal may increase the risk for mortality after hospital discharge.149,150 Further, stopping β-blocker therapy during acute decompensation may lead to lower chronic β-blocker use due to failure to reinstitute β-blocker therapy once the patient has stabilized.150,151 Guidelines recommend continuing β-blocker therapy during hospitalization for HF whenever possible.1,27
Absolute contraindications to β-blocker use include uncontrolled bronchospastic disease, symptomatic bradycardia, advanced heart block without a pacemaker, and acute decompensated HF. However, β-blockers may be tried with caution in patients with asymptomatic bradycardia, COPD, or well-controlled asthma. Particular caution is warranted in patients with marked bradycardia (<55 beats/min) or hypotension (systolic BP <80 mm Hg).
Digoxin Digoxin exerts its positive inotropic effect by binding to sodium- and potassium-activated adenosine triphosphatase (Na, K-ATPase or sodium pump). Inhibition of Na, K-ATPase decreases outward transport of sodium and leads to increased intracellular sodium concentrations. Higher intracellular sodium concentrations favor calcium entry and reduce calcium extrusion from the cell through effects on the sodium–calcium exchanger. The result is increased storage of intracellular calcium in the sarcoplasmic reticulum and, with each action potential, a greater release of calcium to activate contractile elements. Digoxin also has beneficial neurohormonal actions. These effects occur at low plasma concentrations, where little inotropic effect is seen, and are independent of inotropic activity. Unlike other positive inotropes that increase intracellular cyclic adenosine monophosphate (cAMP), digoxin attenuates the excessive SNS activation present in HF patients. Although the precise mechanism is unknown, a digoxin-mediated reduction in central sympathetic outflow and improvement in impaired baroreceptor function appear to play an important role. Because mortality and progression of HF are linked to the extent of SNS activation, these sympathoinhibitory effects may be an important component of the clinical response to the drug. Chronic HF is also marked by autonomic dysfunction, most notably suppression of the parasympathetic (vagal) system. Digoxin increases parasympathetic activity in HF patients and leads to a decrease in HR, thus enhancing diastolic filling. The vagal effects also result in slowed conduction and prolongation of AV node refractoriness, thus slowing the ventricular response in patients with atrial fibrillation. Because atrial fibrillation is a common complication of HF, the combined positive inotropic, neurohormonal, and negative chronotropic effects of digoxin can be particularly beneficial for such patients. The overall response to digoxin is usually an increase in cardiac index and a decrease in PCWP with relatively little change in arterial BP.106,120
Pharmacokinetics Numerous studies of digoxin pharmacokinetics have been published and are summarized in Table 4-11. Digoxin has a large volume of distribution and is extensively bound to various tissues, most notably to Na, K-ATPase in skeletal and cardiac muscles. Because it does not distribute appreciably to body fat, loading doses of digoxin (when necessary) should be calculated based on estimates of lean body weight. There is a long “distribution phase” after administration of oral or IV digoxin, resulting in a lag time before maximum pharmacologic response is observed (see Table 4-11). Transiently elevated SDCs during the distribution phase are not associated with increased therapeutic or adverse effects, although they can mislead the clinician who is unaware of the timing of blood sampling relative to the previous digoxin dose. Consequently, blood samples for measurement of SDCs should be collected at least 6 hours and preferably 12 hours or more after the last dose.
TABLE 4-11 Clinical Pharmacokinetics of Digoxin
In patients with normal renal function, 60% to 80% of a dose of digoxin is eliminated unchanged in urine via glomerular filtration and tubular secretion. The terminal half-life of digoxin is approximately 1.5 days in subjects with normal renal function but approximately 5 days in anuric patients (see Table 4-11). Recent evidence indicates that the drug efflux transporter P-glycoprotein (P-gp) plays an important role in the bioavailability, renal and nonrenal clearance, and drug interactions with digoxin. Clinically important pharmacokinetic/pharmacodynamic drug interactions are summarized in Table 4-12. An extensive review of the pharmacokinetics and pharmacodynamics of digoxin is available.117
TABLE 4-12 Selected Digoxin Drug Interactions
Adverse Effects Digoxin can produce a variety of cardiac and noncardiac adverse effects, but it is usually well tolerated by most patients (Table 4-13).105,120 Noncardiac adverse effects frequently involve the CNS or GI systems but also may be nonspecific (e.g., fatigue or weakness). Cardiac manifestations include numerous different arrhythmias caused by the drug’s multiple electrophysiologic effects (Table 4-13). Cardiac arrhythmias may be the first evidence of toxicity in a patient (before any noncardiac symptoms occur). Rhythm disturbances are of particular concern because patients with chronic HF are already at increased risk for sudden cardiac death, presumably due to ventricular arrhythmias. Patients at increased risk of toxicity include those with impaired renal function, decreased lean body mass, the elderly, and those taking interacting drugs. Hypokalemia, hypomagnesemia, and hypercalcemia will predispose patients to cardiac manifestations of digoxin toxicity. Thus, concomitant therapy with diuretics may lead to electrolyte abnormalities and increase the likelihood of cardiac arrhythmias. Similarly, hypothyroidism, myocardial ischemia, and acidosis will also increase the risk of cardiac adverse effects. Although digoxin toxicity is commonly associated with plasma concentrations greater than 2 ng/mL (2.6 nmol/L), clinicians should remember that digoxin toxicity is based on the presence of symptoms rather than a specific plasma concentration.117 Usual treatment of digoxin toxicity includes drug withdrawal or dose reduction and treatment of cardiac arrhythmias and electrolyte abnormalities. In patients with life-threatening digoxin toxicity, purified digoxin-specific Fab antibody fragments should be administered. SDCs will not be reliable until the antidote has been eliminated from the body.120
TABLE 4-13 Signs and Symptoms of Digoxin Toxicity
Personalized Pharmacotherapy
Pharmacogenetics holds promise for future personalized HF therapy. Most HF pharmacogenetic research has focused on genetic association responses to β-blockers. For example, there is evidence that the β1-adrenergic receptor (ADRB1) Arg389Gly polymorphism is associated with improvement in left ventricular EF with β-blockers.152 Further, the Arg389Gly variant was associated with clinical outcomes with bucindolol, the only β-blocker among those studied in large, randomized, multicenter HF trials that did not significantly improve outcomes.144 The trial with bucindolol was unique in that it included a large number of African American patients. A subgroup analysis showed survival improvement with bucindolol in whites, but not African Americans. African Americans have a higher frequency of the ADRB1 389Gly allele and the α2c-adrenergic receptor (ADRA2C) Del322–325 variant, both of which are associated with a lack of improvement in HF outcomes with bucindolol.153,154 In contrast, the wild-type ADRB1 and ADRA2C genotypes, which occur more often among whites, were associated with a reduced risk for hospitalization and death with bucindolol. The manufacturer of bucindolol sought FDA approval of the drug for patients with the more favorable response genotype; however, their initial efforts have been unsuccessful.
Both metoprolol and carvedilol are also substrates for the cytochrome P450 2D6 enzyme, which is known to be polymorphic. A total of 7% of the white population and 1% to 2% of the Asian American and African American populations who are CYP2D6 poor metabolizers would be expected to have higher plasma concentrations than anticipated at the usual doses of carvedilol and metoprolol. However, given that β-blockers have a wide therapeutic index, it is unclear whether CYP2D6 phenotype significantly impacts hemodynamic and clinical effects.
There is also preliminary evidence of genetic determinants of outcomes with hydralazine/ISDN. Specifically, the endothelial nitric oxide synthase-3 (NOS3) Glu298Asp polymorphism was associated with the effects of hydralazine/ISDN on the composite end point of survival, hospitalization, and quality of life, with greater improvement with the Glu298Glu genotype.155 A separate analysis focused on the gene for corin, a protein expressed in cardiomyocytes that cleaves pro-ANP and proBNP into active natriuretic peptides. The corin Gln568Pro variant leads to a dysfunctional protein and was associated with an increased risk for death or HF hospitalization in the A-HeFT population.156 However, no detrimental effect of the 568Pro variant was observed among patients treated with hydralazine/ISDN, suggesting that the drug combination attenuates the adverse consequences of the 568Pro allele. Both the NOS3 Glu298Glu genotype and corin 568Pro variant occur predominately in persons of African descent, potentially explaining why hydralazine/ISDN is especially effective in African Americans.
Clinical Controversy…
1. Treatment guidelines for SHF recommend that the dose of β-blockers be titrated to those achieved in the clinical efficacy trials. Attainment of these doses is not possible in some patients because of bradycardia, hypotension, or other β-blocker adverse effects. Thus, it is uncertain if these lower doses provide the same benefits as seen when target doses are achieved. Observational data suggest HR reduction may be a more sensitive therapeutic end point than dose as an indicator for the benefits of β-blockers.
2. Patients with SHF and sinus rhythm are at increased risk for stroke and other thromboembolic complications. The optimal approach to antithrombotic therapy (warfarin, aspirin, or no therapy) in these patients remains uncertain. A recent clinical trial showed no difference between warfarin and aspirin for preventing stroke (ischemic or hemorrhagic) or death. The risk of bleeding was higher in patients receiving warfarin compared with that in patients receiving aspirin. The optimal approach to preventing thromboembolic events in these patients remains to be determined.
EVALUATION OF THERAPEUTIC OUTCOMES
Although mortality is an important end point, it does not give a complete measure of the overall impact of this disorder because many patients are hospitalized repeatedly for HF exacerbations and continue to survive, albeit with a significantly reduced quality of life. Thus, some of the more important therapeutic outcomes in HF management, such as prolonged survival or prevention or slowing of the progression of HF, cannot be quantified in an individual patient. However, after appropriate diagnostic evaluation to determine the etiology of HF, ongoing clinical assessment of patients typically focuses on evaluation of three general areas: (a) functional capacity, (b) volume status, and (c) laboratory monitoring.
The evaluation of functional capacity should focus on the presence and severity of symptoms the patient experiences during activities of daily living and how his or her symptoms affect these activities. Questions directed toward the patient’s ability to perform specific activities may be more informative than general questions about what symptoms the patient may be experiencing. For example, patients should be asked if they can exercise, climb stairs, get dressed without stopping, check the mail, go shopping, or clean the house. Another important component of assessment of functional capacity is to ask patients what activities they would like to do but are now unable to perform.
Assessment of volume status is a vital component of the ongoing care of patients with HF. This evaluation provides the clinician important information about the adequacy of diuretic therapy. Since the cardinal signs and symptoms of HF are caused by excess fluid retention, the efficacy of diuretic treatment is readily evaluated by the disappearance of these signs and symptoms. The physical examination is the primary method for the evaluation of fluid retention, and specific attention should be focused on the patient’s body weight, extent of JVD, presence of hepatojugular reflux, presence and severity of pulmonary congestion, and peripheral edema. Specifically, in a patient with pulmonary congestion, monitoring is indicated for resolution of rales and pulmonary edema and improvement or resolution of DOE, orthopnea, and PND. For patients with systemic congestion, a decrease or disappearance of peripheral edema, JVD, and hepatojugular reflux is sought. Other therapeutic outcomes include an improvement in exercise tolerance and fatigue, decreased nocturia, and a decrease in HR. Clinicians also will want to monitor BP and ensure that the patient does not develop symptomatic hypotension as a result of drug therapy. Body weight is a sensitive short-term marker of fluid loss or retention, and patients should be counseled to weigh themselves daily, reporting changes to their healthcare provider so that adjustments can be made in diuretic doses. Patients and healthcare providers should be aware that HF progression may be slowed even though symptoms have not resolved.
Routine monitoring of serum electrolytes and renal function is required in patients with HF. Assessment of serum potassium and magnesium is especially important because hypokalemia and hypomagnesemia are common adverse effects of diuretic therapy and are associated with an increased risk of arrhythmias and digoxin toxicity (hypokalemia). Serum potassium monitoring is also required because of the risk of hyperkalemia associated with ACE inhibitors, ARBs, and aldosterone antagonists. A serum potassium ≥4 mEq/L (≥4 mmol/L) should be maintained with some evidence suggesting it should be ≥4.5 mEq/L (≥4.5 mmol/L).157 Assessment of renal function (BUN and serum creatinine) is also an important end point for monitoring diuretic and ACE inhibitor therapy. Common causes of worsening renal function in patients with HF include overdiuresis, adverse effects of ACE inhibitor or ARB therapy, and hypoperfusion.
Most of these therapeutic end points are incorporated into the ACC/AHA performance measures outlined in Table 4-14.158
TABLE 4-14 ACC/AHA Clinical Performance Measures for Adults with Systolic Heart Failure
ABBREVIATIONS
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Hoyle Leigh
CONTENTS
1.1 Definition ....................................................................3
1.2 Ancient Civilizations ............................................................ 3
1.3 The Mind-Body Philosophy Through the 19th Century ................................. 4
1.4 Psychoanalytic Theory ........................................................... 5
1.5 Studies on Stress ............................................................... 6
1.6 Biopsychosocial Model and Integrative Medicine ...................................... 6
1.7 Evolutionary Medicine .......................................................... 7
1.8 Modern Psychosomatic Medicine .................................................. 7
1.9 Consultation-Liaison Psychiatry Training and Psychosomatic Medicine as a Subspecialty ....................................................... 8
1.10 The Mind-Body Relationship Revisited in the Light of Modern Physics .............................................................. 8
1.1 Definition
Consultation-liaison (CL) psychiatry refers to the skills and knowledge utilized in evaluating and treating the emotional and behavioral conditions in patients who are referred from medical and surgical settings. Many such patients have comorbid psychiatric and medical conditions, and others have emotional and behavioral problems that result from the medical illness either directly or as a reaction to it and its treatment.
Psychosomatic medicine refers to the study of "mind-body" relationship in medicine. Investigators in psychosomatic medicine have historically been interested in the psychosomatic aspects of medical patients, and were pioneer practitioners of CL psychiatry.
1.2 Ancient Civilizations
Imhotep, court physician and architect to King Djoser (2630-2611 BCE) of Egypt, built the Step Pyramid in Sakkhara, Egypt, some 4500 years ago, as a medical instrument to keep the king's body through eons until his soul returned, a truly "psychosomatic" instrument. This pyramid is the oldest pyramid still standing, and Imhotep was deified as god of medicine. Ancient Chinese and Indian medicine was inherently "psychosomatic" in that the psyche and the soma were seen to be intrinsically interconnected. In Chinese medicine, excesses or deficiencies in seven emotions joy, anger, sadness, grief, worry, fear, and fright were commonly considered to cause disease (Rainone, 2000). In Vedic medicine, certain personality components were considered to reside in particular organs, for example, passion in the chest and ignorance in the abdomen, and powerful emotions may cause peculiar behavior.
Hippocrates (470-370 BCE) was perhaps the first physician to systematize clinically the notion that psychological factors affect health and illness. In a famous, what might now be called "forensic psychiatric" opinion, Hippocrates defended a woman who gave birth to a dark-colored baby on the grounds that her psychological impression on seeing an African was sufficient to change the color of her fetus (Zilboorg, 1941). Hippocrates was an excellent clinical observer of psychiatric manifestations of medical disease as shown by his detailed descriptions of postpartum psychosis and delirium associated with tuberculosis and malaria (Zilboorg, 1941). Hippocrates condemned the prevailing view of epilepsy as a "sacred" disease, holding that it was a disease like any other. Though his theory of the "wandering uterus" underlying hysteria lacked scientific foundation, Hippocrates' humoral theory of disease anticipated present-day neurotransmitters. His emphasis on climate, environment, and lifestyle in health and illness, together with his awareness of the role of psychological factors in physical health and his belief in biologic/physiologic explanations of pathogenesis, entitle him to the title of not only the father of medicine, but also the father of psychosomatic medicine and the biopsychosocial approach.
With the descent of the Dark Ages, a tyrannical religious monism attributing mental and physical illness to witchcraft, and divine retribution stifled scientific inquiry. A textbook for the diagnosis (torture) and treatment (execution) of witches was the Malleus Maleficarum (The Witch's Hammer, 1487) written by two Dominican monks, James Sprenger and Henry Kramer, and prefaced with a bull from Pope Innocent VIII.
1.3 The Mind-Body Philosophy Through the 19th Century
The Hippocratic tradition in medicine was revived with the Renaissance and nourished by the Enlightenment. The French mathematician and philosopher Rene Descartes (1596-1650) proposed that the human body was like a machine, subject to objective investigation, while the soul or mind was a separate entity that interacted with the body in the pineal gland and that it was in the domain of theology and religion. This mind-body dualism facilitated the scientific study of the body at the expense of such studies of the mind. A number of competing and complementary theories, briefly described below, have been proposed since then to attempt to explain the nature of mind and body/matter.
Benedictus de Spinoza (1632-1677), a Dutch lens crafter and philosopher, proposed a monism called double aspect theory, that is, the mental and physical are the two different aspects of the same substance, which in his view was God. Gottfried Wilhelm Leibniz (1646-1716) proposed psychophysical parallelism, that is, mind and body exist in parallel harmony predetermined by God from the beginning. Immaterialism, as advocated by George Berkeley (1685-1753), declared that existence is only through perception of the mind, that is, the body is in the mind. On the opposite pole is materialism, which holds that matter is fundamental and that what we call mind is a description of a physical phenomenon. Julien Offroy de la Mettrie (1709-1751) advocated that human souls were completely dependent on the states of the body and that humans were complete automata just like animals as proposed by Descartes.
Epiphenomenalism, proposed by Shadworth Holloway Hodgson (1832-1912), an English philosopher, postulates that the mind is an epiphenomenon of the workings of the nervous system. Mind and emotions, being epiphenomena, cannot affect the physical, just as a shadow cannot affect a person. Thomas Henry Huxley (1825-1895) popularized this view and placed it in an evolutionary context. Double aspect monism, proposed by George Henry Lewes (1817-1878), postulates that the same phenomenon, if seen objectively, is physical, and, if seen subjectively, is mental. William Kingdon Clifford (1845-1879) coined the term mind-stuff theory. In this theory, higher mental functions, such as consciousness, volition, and reasoning, are compounded from smaller "mind-stuff" that does not possess these qualities, and even the most basic material stuff contains some "mind-stuff" so that compounding of the material stuff would produce higher order "mind-stuff." This theory holds psychical monismmind is the only real stuff and the material world is only an aspect in which the mind is perceived.
In spite of strong monistic trends, the major trend in medicine and psychiatry through the 19th and 20th century has remained dualistic and interactional, that is, how the mind affects the body and vice versa. Johann Christian Heinroth (1773-1843) coined the term psychosomatic in 1818 in the context of psychogenesis of physical symptoms. Psychosomatic relationship in the form of hypnosis was demonstrated and exploited by Anton Mesmer (1734-1815), though he mistakenly claimed it to be magnetic in nature ("animal magnetism"). Hypnosis was revived as a subject of medical investigation, diagnostics, and treatment by two competing schools, one at the Salpetriere Hospital in Paris headed by the neurologist, Jean-Martin Charcot (1825-1893), and the other at the university in Nancy, France, led by the internist, Hippolyte Bernheim (1840-1919). Charcot believed that hypnotizability was a result of brain degeneration in hysteria, while Bernheim and the Nancy school (including Ambroise-Auguste Liebeault and Pierre Janet) believed that psychological suggestion underlay the hypnotic phenomena.
1.4 Psychoanalytic Theory
Sigmund Freud (1856-1939) learned hypnosis to treat hysteria under Charcot. Freud gave up hypnosis in favor of free association, and with this tool systematically investigated and proved the psychogenesis of somatic symptoms by reversing them with successful treatment. Franz Alexander (1891-1964) was a student of Sigmund Freud who emigrated to the United States and founded the Chicago Institute of Psychoanalysis in 1932. Alexander psychoanalyzed patients suffering from a variety of somatic illnesses, and formulated that there were seven diseases that were particularly psychosomatic: essential hypertension, peptic ulcer, thyrotoxicosis, ulcerative colitis, neurodermatitis, rheumatoid arthritis, and bronchial asthma. He postulated that specific psychological conflicts were associated with specific autonomic activation, resulting in psychosomatic disease (e.g., in peptic ulcer, repressed dependency needs stimulate gastric secretion causing ulceration). This is called the specificity theory of psychosomatic medicine. Flanders Dunbar (1902-1959), a contemporary of Alexander, believed that psychosomatic illnesses were associated with certain personality profiles and constellations rather than specific conflicts.
Peter Sifneos and John Nemiah (1971, 1996) proposed that psychosomatic disorders arose as a result of a difficulty in describing or recognizing one's own emotions, a limited fantasy life, and general constriction in the affective life, which they called alexithymia. The concrete mode of thinking associated with alexithymia is called operational thinking or pensee operatoire. Alexithymia is postulated to be related to primitive defenses of denial and splitting, and may be associated with a disturbance in cerebral organization.
Psychological defense mechanisms have been shown to be essential in modulating psychophysiologic arousal to stress.
During the latter half of the 20th century, through the work of various investigators, specificity theory gave way to a field model of psychosomatic medicine in which biological constitution interacts with environment in the development of personality, which, in turn, interacts with current stress in health and disease (Mirsky et al., 1957; Leigh and Reiser, 1992).
1.5 Studies on Stress
The American physiologist Walter Cannon (1871-1945) investigated the physiologic activation associated with the fight flight reaction and the role of homeostasis in physiology. Hans Selye (1907-1982) systematically studied stress that led to the elucidation of the general adaptation syndrome through the activation of the hypothalamic-pituitary-adrenal (HPA) axis. Later in the 20th century with the development of psychoneuroendocrinology and psychoimmunology, there has been an explosion of knowledge on the relationship between stress and all aspects of the human organism.
1.6 Biopsychosocial Model and Integrative Medicine
George Engel (1913-1999), a well-known psychosomatic investigator, coined the term biopsychosocial model (Engel, 1977), as an alternative to the prevailing disease model in medicine that he called the biomedical model. While recognizing the contributions that the biomedical model made to the development of modern medicine, Engel objected to the "dogma" of the biomedical model on the grounds that it is reductionistic, mechanistic, and dualistic. Utilizing a general systems theory approach, the biopsychosocial model proposes that psychosocial factors influence the pathogenesis of all diseases. The biopsychosocial model has found wide acceptance among psychiatrists and medical educators.
In late 20th century, the terms behavioral medicine and integrative medicine appeared. Behavioral medicine is practically indistinguishable from psychosomatic medicine except that, in treatment modalities, it tends to incorporate more behavioral techniques such as biofeedback. Integrative medicine strives to incorporate within the biopsychosocial model approaches derived from nonorthodox medicine such as alternative and complementary medicine.
1.7 Evolutionary Medicine
Charles Darwin (1809-1882) showed that species evolved through the process of natural selection (The Origin of Species, 1859). With modern advancements of genome analysis, it is now possible to calculate just how closely specific species are related. For example, humans and chimpanzees share almost 99% of the genes. An evolutionary perspective of human illness is shedding light on why illnesses arise. As natural section confers advantage to traits only up to the reproductive age, healthy traits in the post-reproductive period are not selected for. The human body probably evolved so that it was best adapted for the Stone Age, when most adults died in their youth. With the prolongation of human life that came with the progress of civilization and medical advances, the human body is living long past what it was adapted for (Nesse and Williams, 1996). The Stone-Age adapted human body may be ill-adapted for modern life, with its abundance of food, lack of physical exercise, and mental stresses, especially in the post-reproductive age. Evolutionary perspectives also may explain why certain genes that may cause vulnerability to potential mental illness, such as panic, may be adaptive under certain conditions found in evolutionary history (e.g., survival value, as in an overly sensitive smoke-detector).
1.8 Modern Psychosomatic Medicine
Advances in molecular genetics and imaging technology have elucidated the role of genes in our constitution, brain morphology, and behavior. Psychoneuroendocrinology and psychoneuroimmunology have elucidated the mechanism by which stress affects the human organism. Health and illness is now conceptualized as a result of the interactions among genes, early environment, personality development, and later stress (see Chapter 6). This interaction is in no small measure influenced by salutary factors such as good early nurturance and current social support. It is also clear that all illnesses are the results of this interaction, that there is no subset of illnesses that are any more psychosomatic than others. Nevertheless, the term psychosomatic continues to be used to denote studies and knowledge that place particular emphasis on psychosocial factors in medical illness.
Some consider psychosomatic medicine to denote an interdisciplinary approach that includes internists, oncologists, psychologists, etc., in contrast to consultation-liaison psychiatry, which is clearly a field within psychiatry.
There are a number of national and international "psychosomatic" organizations such as the American Psychosomatic Society, Academy of Psychosomatic Medicine, European Society of Psychosomatic Medicine, and International College of Psychosomatic Medicine, and "psychosomatic" journals such as Psychosomatic Medicine, Psychosomatics, Journal of Psychosomatic Research, and Psychotherapy and Psychosomatics. General Hospital Psychiatry, International Journal of Psychiatry in Medicine, and Psychosomatics are mainly consultationliaison psychiatry journals. Most of the organizations and journals are interdisciplinary, participated in by members of various specialties and professions. In Europe and Japan, there is often a department of psychosomatic medicine in medical schools, apart from the psychiatry department. Such psychosomatic departments mainly deal with patients with psychophysiologic disorders, and may use complementary medicine techniques such as yoga and meditation.
In the United States, the term psychosomatic medicine is often used interchangeably with consultation-liaison psychiatry, and most CL psychiatrists practice in general hospital settings evaluating and treating psychiatric, emotional, and behavioral problems of medical patients. Research in the emotional aspects of specific medical patients gave rise to such fields as psychonephrology, psycho-oncology, and psychodermatology.
1.9 Consultation-Liaison Psychiatry Training and Psychosomatic Medicine as a Subspecialty
In the early part of the 20th century, formal training in CL psychiatry began in a number of general hospitals, most notably at the University of Rochester under George Engel's direction and at the Massachusetts General Hospital (MGH) under Thomas Hackett's direction. Other notable training sites included University of Cincinnati, Montefiore Hospital-Albert Einstein Medical College in New York, and Yale-New Haven Hospital. The Rochester model was psychodynamically oriented, and trained both psychiatrists and internists in "liaison psychiatry." Liaison psychiatry emphasized the educational role, and the trainee was assigned to be a member of the primary medical team including making rounds together. The MGH model, in contrast, emphasized the consultation aspect of training. The training programs were usually one to two years in duration. The CL training programs thrived during the 1960s and 1970s with the support of the National Institute of Mental Health and James Eaton, then head of its education branch. With the advent of managed care, however, "unbillable" liaison activity has faded to a large extent.
In 2003, the American Board of Psychiatry and Neurology (ABPN) approved the issuance of certificates in psychosomatic medicine. The Academy of Psychosomatic Medicine, an organization of CL psychiatrists, had been advocating the recognition of a subspecialty for CL psychiatry for some time. The executive summary of the proposal submitted to the ABPN states:
This application is in response to the growing body of scientific evidence demonstrating the high prevalence of psychiatric disorders in patients with medical, surgical, obstetrical, and neurological conditions, particularly for patients with complex andlor chronic conditions ("the complex medically ill"), and the critical importance of addressing these disorders in managing their care. [Psychosomatic medicine] psychiatrists would, therefore, constitute a group of individuals in psychiatry who have specialized expertise in the diagnosis and treatment of psychiatric disorders/difficulties in complex medically ill patients.
Obviously, this is a description of CL psychiatry. It is ironic that psychosomatic medicine, rather than CL psychiatry, is now recognized as a subspecialty of psychiatry as this designation leaves nonpsychiatric "psychosomaticists" in a Neverland.
1.10 The Mind-Body Relationship Revisited in the Light of Modern Physics
The advances in medicine during the past several decades have been largely due to the elucidation of the mechanisms of pathogenesis based on genetics, the role of stress, and functional morphology. At a philosophical level, the psyche of psychosomatic medicine is understood as a label for brain function, particularly of the prefrontal cortex. While this newtonian conceptualization of the mind works at a heuristic level, developments in modern physics may require us to reexamine this epiphenomenologic view of the mind.
Sperry (1969, 1980) proposes that mental phenomena have dynamic emergent properties arising from cerebral excitation, which are different from and more than material brain processes. Once generated from neural events, the higher order mental patterns and programs have their own subjective qualities, and progress, operate, and interact by their own causal laws that cannot be reduced to neurophysiology. Popper and Eccles (1981) maintain that mental processes are emergent relative to physical processes but believe in a dualism where the relationship of the brain to the body is that of the computer to the programmer, with the self-conscious mind playing a superior interpretive role.
Software written in binary language is both patterns of magnetic or optical properties as well as information, as defined with the interacting entity (without interaction there is no communication and no information). How do these entities become interactional (communicational)? Such interaction may be inherent in nature, as matter and antimatter "know" to annihilate each other upon encounter. Psychological awareness, although a subset of communication (interaction), might arise as an emergent phenomenon in a complex system of lower level interactions. Perhaps, as a critical mass of uranium will start a chain reaction, a "critical mass" of "proto-awareness" might result in a series of events leading to what we call awareness. To the extent that humans can hardly guess at the experience of "awareness" of beings such as photons, electrons, or, for that matter, dogs and chimpanzees, a true description of others' awareness may be an impossible task. Nevertheless, whether mental or physical, information is exchanged at all levels of organization in the cosmos.
Modern quantum theory presents us some intriguing notions of the mind. Quantum mechanics places the conscious observer at the center of reality. It is a quantum theory maxim that "no phenomenon is a phenomenon unless it is an observed (or recorded, resulting in some irreversible change) phenomenon." Until observation has occurred, reality exists only as potentials or probabilistic waves. At the instant of observation, however, the wave function collapses into a reality according to the orthodox Copenhagen interpretation (Bohr, 1958), or the universe splits into a number of possible universes according to the many worlds theory (Everett, 1973; Wolf, 1988). Consciousness, though arising as a result of brain processes, may be regarded as a cosmic process of creation (as the choices it makes are not locally determined but cosmically inherent) that produces events or reality (Stapp, 1993). Such events, or the observation-induced collapse of the wave function into particles, seem to supersede the barriers of space-time.
Einstein proposed an experiment that tried to show what he considered to be a failing in quantum theory: Suppose two particles arising from an interaction are flying apart at the speed of light. According to quantum theory, if one quality of the particle is observed at a later time (say, a particular spin to the left) at one place by observer A, another observer B, observing the other particle (say, 20 light years away from observer A) must observe the complementary quality that is being observed by A. As it is purely by chance that A would observe the spin to the left, until the moment of observation of A, the spin of B is indeterminate. But once A is observed, B's spin can be nothing but "right," which Einstein considered to be "spooky action at a distance" at speeds faster than light the Einstein-Podolsky-Rosen (EPR) paradox (Einstein et al., 1935). Later reformulation of the EPR experiment (Bell's inequality; Bell, 1964) that was carried out by Aspect et al. (1982) proved the quantum theory predictions over Einstein's objections. It should be pointed out, however, that the quantum theory predictions do not presuppose "communication faster than light." It simply shows a cosmic connectedness or unity beyond space-time separation. One way of looking at this is to consider the two particles not to be separate at all, but a part of a whole (a single wave). This is compatible with modern superstring and Membrane or M-theories (Greene, 2004).
In playing a role as to when and how observation is done, a series of conscious choices influence the way reality occurs (wave function collapses), or biases the number of split-off universes in a particular direction and therefore the probability that observers will find themselves in a universe in the chosen direction (in a many-worlds interpretation).
In this regard, it may be useful to ponder the role of the observing physician in the diagnosis and treatment of disease and in patient care. Will the act of diagnosis result in a collapse of the wave function? What is the role of a patient's will (or choice) to live, which may arise out of an interaction between the patient and the physician or the family and friends?
The practice of medicine may truly be a creative process. The interaction between the physician and the patient creates new paths of reality for both participants.
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