Jo E. Rodgers and Brent N. Reed
KEY CONCEPTS
Unlike chronic heart failure therapies whose primary role is to improve survival, treatment goals for acute decompensated heart failure (ADHF) are directed toward relief of congestive symptoms, restoration of systemic oxygen transport and tissue perfusion through improved myocardial contractility, and minimization of further cardiac damage and other adverse effects.
Maximizing oral chronic heart failure therapy may assist with optimizing cardiac output and relieving congestion.
Patients presenting to the hospital with ADHF can be categorized into four subsets based upon fluid status (euvolemic or “dry” vs. fluid overloaded or “wet”) and cardiac function (adequate cardiac output or “warm” vs. hypoperfusion or “cold”). Therefore, patients are either warm and dry, warm and wet, cold and dry, or cold and wet.
While invasive hemodynamic monitoring using a PA catheter does not alter outcomes in a broad population of ADHF patients, it is indicated in those who are refractory to initial therapy, whose volume status is unclear, or who have clinically significant hypotension (i.e., systolic blood pressure less than 80 mm Hg) or worsening renal function despite therapy.
Key hemodynamic parameters to monitor with a PA catheter include pulmonary capillary wedge pressure (PCWP; reflecting fluid status or “preload”), cardiac output or cardiac index (CI; reflecting the innate contractility of the heart), and systemic vascular resistance (reflecting vascular tone or “afterload”). While a normal PCWP (6 to 12 mm Hg) is desirable in healthy patients, higher filling pressures (15 to 18 mm Hg) are often necessary in patients with heart failure.
Three major therapeutic categories exist for the management of ADHF including diuretics, inotropes, and vasodilators. No therapy studied to date has conclusively been shown to decrease mortality and several may potentially worsen outcomes.
IV loop diuretics are considered first-line therapy for the management of ADHF associated with fluid overload nonresponsive to orally administered diuretics. While a variety of therapeutic options may be considered for refractory fluid overload, a recent clinical trial demonstrated no difference in outcomes between bolus and continuous administration of IV diuretics; however, administering high-dose IV diuretic (2.5-times the previous oral regimen) is associated with greater fluid removal rate. If patients continue to be refractory to, or experience worsening renal function with diuretic therapy, vasodilatory and inotropic therapy may be indicated. Placement of a pulmonary artery (PA) catheter may be helpful in guiding therapy in such patients.
IV inotropes are recommended for symptom relief or end-organ dysfunction in patients with left ventricular dysfunction and low cardiac output. Such therapy may be especially useful in patients with low systolic blood pressure (less than 90 mm Hg) or symptomatic hypotension in the setting of adequate filling pressures. Inotropic therapy may also be considered in patients who do not tolerate or respond to IV vasodilators or in patients with worsening renal function, but should be avoided in patients with reduced left heart filling pressures. Patients receiving these agents should be monitored continuously for arrhythmias.
Given the potential risks associated with inotropic therapy, vasodilators should be considered prior to their use.
IV vasodilators may be added to diuretics for rapid symptom resolution, especially in patients with acute pulmonary edema or severe hypertension. Such therapy may also be considered in patients who fail to respond to aggressive treatment with diuretics. Vasodilators should be avoided in patients with symptomatic hypotension and frequent blood pressure monitoring is necessary to ensure their safe use. In addition, these agents should not be used in patients with reduced left heart filling pressures. If patients fail to respond to IV diuretics or vasodilators or experience worsening renal function, IV inotropic therapy should be considered.
Vasopressin antagonists provide a new therapeutic option for managing hyponatremia in patients with euvolemic or hypervolemic hyponatremia. Tolvaptan is the only vasopressin antagonist indicated for hyponatremia associated with heart failure. Despite being an oral agent, tolvaptan should only be initiated in the hospital setting to allow for monitoring of volume status and serum sodium concentrations, as rapid correction of serum sodium may result in adverse neurological sequalae.
Given extended wait times for patients on the cardiac transplantation list, implantation of a ventricular assist device may be considered for those in whom extended time to identify a suitable donor is anticipated (i.e., “bridge” to transplant) or in whom transplantation is not an option (i.e., “destination” therapy).
INTRODUCTION
As discussed in the Systolic and Diastolic Heart Failure chapter (Chap. 4), the number of patients with heart failure (HF) is substantial and continues to increase. Despite survival from HF having improved over time, the 5-year mortality rate remains 50%. In addition, the growing number of patients with this disorder and the progressive nature of the disease have led to substantial increases in hospitalizations for HF. In addition, an estimated 5.1 million U.S. adults over 20 years of age have HF; it is estimated that by 2030, an additional 3 million people will have HF, representing a 25% increase in prevalence from 2013 estimates. At 40 years of age, the lifetime risk for developing HF is one in five in both men and women. Recent data indicate that over 1 million patients are hospitalized for HF annually, resulting in significant morbidity, mortality, and consumption of large quantities of healthcare resources.1,2Hospital admission for HF is associated with an increased risk of subsequent hospitalization and decreased survival.3 The economic impact of heart failure is considerable with costs driven primarily by inpatient care.2
A number of terms have been used to characterize patients with worsening heart failure requiring hospitalization. Patients with persistent symptoms or refractory heart failure requiring specialized interventions despite optimal oral therapies are classified as Stage D in the American College of Cardiology/American Heart Association (ACC/AHA) classification scheme.4–6 These patients typically fall into the category of New York Heart Association (NYHA) class III or IV. Specialized interventions may include the addition of select medications beyond standard therapy or consideration for various surgical options. The terms acute decompensated heart failure (ADHF) or exacerbation of heart failure refer to those patients with new or worsening signs or symptoms (often as a result of volume overload and/or hypoperfusion) requiring additional medical care such as emergency department visits and hospitalizations. The term acute heart failure may be misleading as it more often refers to the patient with a sudden onset of signs or symptoms in the setting of previously normal cardiac function. This chapter will focus on the management of patients with ADHF. Clinical syndromes within decompensated heart failure include pulmonary or systemic volume overload, low cardiac output, and acute pulmonary edema. Clinicians should recognize that patients may present with impaired or preserved left ventricular systolic function and a variety of etiologies may be responsible for the primary disease process. The clinical course of heart failure manifests as periods of relative stability with an increasing frequency in episodes of decompensation as the underlying disease progresses.7
Despite the considerable morbidity and mortality associated with ADHF, the first randomized placebo-controlled trials in this patient population were published in 2002.8,9 In addition, it was not until 2005 that guidelines specifically addressing ADHF were promulgated. The Heart Failure Society of America (HFSA) and the ACC/AHA guidelines address the management of ADHF; however, the HFSA guidelines are more detailed and will be the focus of the remainder of this chapter.4,6,10
PATHOPHYSIOLOGY AND CLINICAL PRESENTATION
Patients requiring intensive therapy for ADHF may have a variety of underlying etiologies and clinical presentations.10 Patients with worsening chronic heart failure comprise approximately 70% of heart failure hospitalizations. These patients can become refractory to oral therapies and decompensate following even a relatively mild insult (e.g., dietary indiscretion, nonsteroidal antiinflammatory drug use), medication noncompliance, or a concurrent noncardiac illness (e.g., infection). New or worsening cardiac processes, such as myocardial infarction, atrial fibrillation, hypertensive urgency/emergency, myocarditis, or acute valvular insufficiency may also result in decompensation in an otherwise stable patient. Secondly, de novo heart failure may occur when left ventricular dysfunction results from a large myocardial infarction or sudden elevation in blood pressure; such cases represent approximately 25% of admissions. A third group of patients with severe left ventricular systolic dysfunction associated with progressive worsening of cardiac output and refractoriness to therapy represents about 5% of heart failure admissions.11 Additional insight into the clinical characteristics of patients presenting unexpectedly with ADHF indicates that a high percentage have hypertension and preserved left ventricular systolic function.12
Several studies have provided a better understanding of the prognostic factors associated with ADHF. Data from the Acute Decompensated Heart Failure National Registry (ADHERE), an archive of hospitalized patients with a primary diagnosis of ADHF, found blood urea nitrogen (BUN) greater than or equal to 43 mg/dL (15.4 mmol/L) to be the best individual predictor of in-hospital mortality, followed by systolic blood pressure less than 115 mm Hg and serum creatinine greater than or equal to 2.75 mg/dL (243 μmol/L). Using these three parameters, patients may be identified as low, intermediate, high, and very high risk with in-hospital mortalities of 2%, 6%, 13%, and 20%, respectively.13 Hyponatremia, elevations in troponin I, ischemic etiology, and poor functional capacity are also negative prognostic factors.11 Importantly, patients who survive a hospitalization for ADHF remain at high risk for rehospitalization or death. Data from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) Registry, another archive of ADHF patients, indicated overall mortality and rehospitalization rates of 8.6% and 29.6%, respectively, at 60 to 90 days postdischarge.14 In patients who survive a hospitalization for ADHF, low blood pressure and poor renal function are also negative prognostic markers for subsequent readmission or death.14 However, use of standard heart failure therapies at discharge as well as coronary angiography or implantable cardioverter-defibrillator placement during hospitalization are associated with improved prognosis,14 suggesting that optimal management of these patients during their hospitalization can yield beneficial effects on subsequent prognosis.
GENERAL APPROACH TO TREATMENT
The overall goals of therapy in ADHF are to provide symptomatic relief while optimizing volume status and low cardiac output so that a patient can be discharged in a stable compensated state on oral drug therapy. Although diuretic, vasodilator, and positive inotropic therapy can be very effective at achieving these goals, their efficacy must be balanced against the potential for serious toxicity. Thus, another important goal is to minimize the risks associated with these therapies including renal dysfunction, myocardial injury, electrolyte depletion, hypotension, and arrhythmias.
In addition, all patients should be evaluated for potential etiologies contributing to decompensation as well as other precipitating factors, including atrial fibrillation and other arrhythmias, worsening hypertension, myocardial ischemia or infarction, anemia, hypothyroidism or hyperthyroidism, or other causes. Medications (including noncardiac medications) that may worsen cardiac function should also be considered as precipitating or contributing factors. Patients who may benefit from coronary revascularization should also be identified. Prior to discharge, optimization of chronic oral therapy and patient education are critical to preventing future hospitalizations. When available and appropriate, patients should be referred to a heart failure disease management program.10
A careful history and physical examination are key components in the diagnosis of ADHF. The history should focus on the potential etiologies of heart failure, the presence of any precipitating factors, onset, duration, and severity of symptoms, and a careful medication history. Current guidelines recommend making the diagnosis of ADHF based primarily on signs and symptoms.10 The more common presentation of ADHF is severe fluid overload, and orthopnea is the symptom that best correlates with elevated pulmonary pressures.15 Important elements of the physical examination include assessment of vital signs and weight, cardiac auscultation for heart sounds and murmurs, pulmonary auscultation for rales, and evaluation for the presence of peripheral edema. Jugular venous pressure is the most reliable indicator of volume status and should be carefully evaluated on admission and closely followed during hospitalization as an indicator of the efficacy of diuretic therapy.15 An S3 gallop, suggestive of increased volume in the left ventricle, has high diagnostic specificity for heart failure decompensation.16 Other physical findings such as pulmonary crackles and lower extremity edema have low specificity and sensitivity for the diagnosis of ADHF. The development of a bedside assay for plasma B-type natriuretic peptide (BNP) has focused considerable attention on the use of natriuretic peptide levels as an aid in the diagnosis of suspected heart failure.17 Plasma BNP and N-terminal pro-BNP concentrations are positively correlated with the degree of left ventricular dysfunction and heart failure, and these assays are now frequently used in acute care settings to assist in the differential diagnosis of dyspnea (heart failure vs. asthma, chronic obstructive pulmonary disease, or infection). A low BNP concentration, often defined as less than 100 pg/mL (ng/L; 29 pmol/L), has a 96% predictive value for excluding heart failure as the underlying etiology of a patient presenting with dyspnea. In addition, an elevated BNP concentration prior to discharge is associated with an increased risk of poor long-term outcomes. However, some limitations exist with the use of BNP. For example, any disease process that increases right heart pressures will elevate BNP, including pulmonary emboli, chronic obstructive lung disease, and primary pulmonary hypertension. In addition, BNP concentrations may be mildly increased with advanced age, female gender, and renal dysfunction, and lower in the setting of obesity.15 Although ongoing research will better characterize the role of BNP in the diagnosis and treatment of heart failure, current guidelines recommend obtaining a BNP concentration in conjunction with assessing signs and symptoms when the diagnosis of ADHF is uncertain.10
Hospitalization for ADHF is recommended or should be considered depending on patient presentation (Table 5-1). Most patients do not require admission to an intensive care unit and may be admitted to a monitored unit or general medical floor. If a patient experiences hemodynamic instability necessitating frequent monitoring of vital signs, invasive hemodynamic monitoring, or rapid titration of IV medications (with concurrent monitoring), admission to an intensive care unit may be required to assure safe and effective outcomes.
TABLE 5-1 Recommendations for Hospitalizing Patients Presenting with ADHF
The first step in the management of ADHF is to ascertain that optimal treatment with oral medications has been achieved.10 If fluid retention is evident on physical examination, aggressive diuresis should be pursued. Although increasing the dose of oral diuretic therapy may be effective in some cases, the use of IV diuretics is often necessary. Every effort should be made to optimize standard heart failure therapy including an ACE inhibitor and β-blocker. β-blocker therapy should generally be continued during a hospitalization unless recent dose initiation or uptitration was responsible for decompensation. In such cases, β-blocker therapy may be temporarily held or dose-reduced. Otherwise, discontinuation of β-blockers is discouraged as it has been associated with worse outcomes in patients in ADHF.18,19Appropriateness of initiating β-blockers prior to discharge will be discussed later in this chapter.
Discontinuation of ACE inhibitor or β-blocker therapy may be necessary in the setting of cardiogenic shock or symptomatic hypotension. Certain therapies may also need to be temporarily held in the setting of renal dysfunction, especially in the setting of oliguria or hyperkalemia (e.g., ACE inhibitor, angiotensin receptor blocker, aldosterone antagonist) or elevated serum digoxin concentrations. Therapies that can cause worsening renal function (e.g., ACE inhibitor) should only be initiatied or uptitrated cautiously during aggressive fluid removal with IV diuretic therapy. In addition, serum potassium concentrations should be monitored closely as IV diuretic therapy is transitioned to oral diuretic therapy, especially if an aldosterone antagonist was initiated during the hospital stay; this ensures such therapy can be tolerated on the oral diuretic dose prescribed at discharge. Most patients may continue to receive digoxin at low doses targeting a trough serum concentration of 0.5 to 1 ng/mL (0.6 to 1.3 nmol/L).10 Discontinuation of digoxin is generally discouraged as an association between withdrawal of therapy and worsening HF has been well-documented.20,21 Digoxin should only be discontinued if serum concentrations cannot be maintained in a desirable range.
Two general approaches exist for maximizing therapy in the ADHF patient. One is to use simple clinical parameters (e.g., signs and symptoms, blood pressure, renal function) and the other is to combine these parameters with invasive hemodynamic monitoring. In all ADHF patients, close monitoring is essential for ensuring an optimal response to therapy while avoiding adverse effects (summarized in Table 5-2). Daily monitoring to assess the efficacy of drug therapy should include weight, strict fluid intake and output, and heart failure signs and symptoms. Foley catheter placement is not recommended unless close monitoring of urine output is not otherwise possible. As safety endpoints, monitoring for electrolyte depletion, symptomatic hypotension, and renal dysfunction should be assessed frequently. While many of the above parameters may be monitored daily, some will need to be monitored more frequently as dictated by patient clinical status. Vital signs should be assessed multiple times throughout the day at a frequency that is appropriate for the patient’s degree of stability. Orthostatic blood pressure should be assessed at least once daily.10
TABLE 5-2 Monitoring Recommendations for Patients Hospitalized with ADHF
PRINCIPLES OF THERAPY BASED ON CLINICAL PRESENTATION
Appropriate medical management of ADHF is guided by determining whether the patient has signs and symptoms of fluid overload (“wet” heart failure) or low cardiac output (“cold” heart failure).15,22As previously discussed, most patients present with fluid overload (or the “wet” profile). Symptoms consistent with pulmonary congestion include orthopnea and dyspnea with minimal exertion and those of systemic congestion include GI discomfort, ascites, and peripheral edema. Patients with no or minimal fluid overload (or the “dry” category of ADHF) may have symptoms that are more difficult to distinguish. Such patients may present with a syndrome of low cardiac output (“cold” heart failure) which is characterized principally by extreme fatigue as well as poor appetite, nausea, and early satiety, although GI symptoms may be a sign of congestion rather than low cardiac output to the GI tract. Patients with “cold” heart failure frequently exhibit worsening renal function and a decline in serum sodium concentrations, which, as previously discussed, are both associated with poor prognosis.
Many patients will present with signs and symptoms of both wet and cold types of ADHF. In these patients, low-output symptoms may not be obvious until congestion is optimally treated.
PRINCIPLES OF THERAPY BASED ON HEMODYNAMIC SUBSETS
Patients with ADHF may have critically reduced cardiac output, usually with low arterial blood pressure and systemic hypoperfusion resulting in organ system dysfunction (i.e., cardiogenic shock). They may also have pulmonary edema with hypoxemia, respiratory acidosis, and markedly increased work of breathing. With cardiopulmonary support, response to interventions should be assessed promptly to allow for timely adjustments in treatment. Since cardiopulmonary support must be instituted and adjusted rapidly, immediate assessment of each intervention limits risks and allows for more prompt adjustments in therapy. Continuous monitoring of ECG, continuous pulse oximetry, urine flow, and automated blood pressure recordings are standards of care for critically ill patients with cardiopulmonary decompensation. Peripheral or femoral arterial catheters may be utilized for continuous and accurate assessment of arterial pressure.
Hemodynamic Monitoring
The role of invasive hemodynamic monitoring in patients with ADHF remains controversial. In a clinical trial assessing the routine use of this strategy, PA catheter placement had no impact on survival after hospital discharge, although patients with a clear indication for its use were excluded.23 Based on these results, the routine use of invasive monitoring is not currently recommended. However, invasive monitoring often provides essential information for adjusting drug therapy in patients with a confusing or complicated clinical picture and during dose titration of rapidly acting medications. Therefore, invasive monitoring should be considered in patients who are refractory to initial therapy, those in whom volume status is unclear, or those who have clinically significant hypotension (e.g., systolic blood pressure less than 80 mm Hg) or worsening renal function despite therapy. In addition, documentation of an adequate hemodynamic response to inotropic therapy is often necessary prior to committing patients to chronic outpatient inotropic therapy.10 Finally, assessment of hemodynamic parameters is required to document adequate reversal of pulmonary hypertension prior to cardiac transplantation.15
Invasive hemodynamic monitoring is usually performed with a flow-directed PA catheter (also known as Swan-Ganz catheter) placed percutaneously through a central vein and advanced through the right side of the heart and into the PA. Inflation of a balloon proximal to the end port allows the catheter to “wedge,” yielding the PA occlusion pressure, which estimates the pulmonary venous (left atrial) pressure and, in the absence of intracardiac shunt, mitral valve disease or pulmonary disease, the left ventricular end-diastolic pressure. While the term pulmonary artery occlusion pressure has previously been used to describe the filling pressure of the heart, the term pulmonary capillary wedge pressure (PCWP) is used more commonly in clinical practice and will be used henceforth. The PCWP is a useful marker of volume status; an elevated PCWP indicates fluid overload while a reduced PCWP indicates dehydration or inadequate filling pressures. Cardiac output may also be measured and represents the volume of blood being pumped by the heart (in particular by the left ventricle) in a minute. The cardiac index (CI) normalizes the cardiac output for body surface area, thus allowing measurements of heart performance to be made without being influenced by body size. Systemic vascular resistance is calculated using cardiac output and thus is inversely related to cardiac output. Mixed venous oxygen saturation represents the end result of both oxygen delivery and consumption at the tissue level.
Systemic vascular resistance (also referred to as total peripheral resistance) reflects the “afterload” or resistance applied to the left ventricle, which represents the force impeding ejection of blood from the left ventricle. Vasoconstriction (i.e., decrease in blood vessel diameter) increases vascular resistance, whereas vasodilation decreases it. An elevated systemic vascular resistance is common in untreated heart failure and is generally responsive to oral or IV arterial vasodilators. Conversely, a reduction in resistance is consistent with vasodilatory shock (e.g., sepsis) and is routinely managed with IV vasopressor therapy. In lieu of inotropic therapy, arterial vasodilators are the therapy of choice to reduce elevated systemic vascular resistance in ADHF.
Resistance present in the vasculature of the lungs is known as the pulmonary vascular resistance, and represents the impedance of blood flow from the right ventricle to the pulmonary circulation. Pulmonary hypertension and pulmonary edema are two common causes of elevated pulmonary vascular resistance. Patients with pulmonary hypertension must have proven reversibility in elevated pulmonary pressures prior to being listed for heart transplantation. If these pressures are irreversible, isolated right ventricular failure is likely to occur immediately following heart transplantation. Just as systemic resistance is calculated using mean arterial pressure, pulmonary vascular resistance is calculated using mean PA pressure, which incorporates the PA systolic and diastolic pressures. The PA diastolic pressure may be useful if the PA catheter fails to wedge (making it impossible to obtain PCWP). If PCWP and PA diastolic pressure correlate prior to the failure to wedge, then PA diastolic pressure can be followed as a surrogate marker of fluid status. Normal values for hemodynamic parameters are listed in Table 5-3.
TABLE 5-3 Hemodynamic Monitoring: Normal Values
In addition to understanding the initial clinical presentation, invasive hemodynamic monitoring assists with the classification of patients into specific subsets and subsequent selection of appropriate medical therapy. These hemodynamic subsets were first proposed for patients with left ventricular dysfunction following an acute myocardial infarction but also are applicable to patients with acute or severe heart failure from other causes (Fig. 5-1).24 This classification scheme has four subsets and is based on a CI above or below 2.2 L/min/m2 (0.037 L/s/m2) and a PCWP above or below 18 mm Hg. A treatment algorithm, based on hemodynamic subsets, is provided in Figure 5-2. In addition to utilizing the above profiles or categories to stratify patients with ADHF, these four hemodynamic profiles are also predictive of clinical outcomes. Patients in the wet-warm and wet-cold profiles have a twofold and 2.5-fold greater risk of death at 1 year, respectively, compared to dry-warm patients.15 Patients may experience compromised CI in the setting of significant fluid overload, which may improve as diuresis occurs. The underlying mechanism for how increasing fluid overload further worsens cardiac function is not clearly understood and is depicted in Figure 5-3.
FIGURE 5-1 Hemodynamic subsets of heart failure based on cardiac index and pulmonary artery occlusion pressure. Cardiac index is expressed in conventional units of mL/min/m2, and can be converted to SI units of mL/s/m2 by multiplying by 0.0167. (Forrester JS, Diamond G, Chatterjee K, et al. Medical Therapy of Acute Myocardial Infarction by Application of Hemodynamic Subsets. N Engl J Med 1976;295:1356–1362. Copyright © 1976 Massachusetts Medical Society. All rights reserved.)
FIGURE 5-2 General treatment algorithm for ADHF based on clinical presentation. IV vasodilators that may be used include nitroglycerin, nesiritide, or nitroprusside. Metolazone or spironolactone may be added if the patient fails to respond to loop diuretics and a second diuretic is required. IV inotropes that may be used include dobutamine or milrinone. (CI, cardiac index; CTZ, chlorothiazide; HCTZ, hydrochlorothiazide; HF, heart failure; MAP, mean arterial pressure; PAC, pulmonary artery catheter; PCWP, pulmonary capillary wedge pressure; PO, by mouth; SBP, systolic blood pressure.) Adapted from HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Cardiac Fail 2010;16:e1–e2.
FIGURE 5-3 Relationship between cardiac output (shown as cardiac index which is CO/BSA) and preload (shown as pulmonary capillary wedge pressure). Cardiac index is expressed in conventional units of mL/min/m2, and can be converted to SI units of mL/s/m2 by multiplying by 0.0167.
Subset I
Patients in hemodynamic subset I have a CI and PCWP within generally acceptable ranges and have the lowest mortality of any subset. These patients do not need immediate specific interventions other than maximizing oral therapy and monitoring. Patients with significant left ventricular dysfunction may still present in subset I because normal compensatory mechanisms and/or appropriate drug therapy may at least partially correct an otherwise abnormal hemodynamic profile.
Subset II
As shown in Figure 5-1, patients in subset II have an adequate CI but a PCWP greater than 18 mm Hg. These patients are likely to have congestion (i.e., “wet” heart failure) secondary to increased hydrostatic pressure in the pulmonary and systemic circulation but no evidence of peripheral hypoperfusion. The primary goal of therapy in these patients is to reduce congestion by lowering PCWP without reductions in cardiac output, increases in heart rate, or further neurohormonal activation. Therefore, it is critically important that PCWP not be decreased excessively. Although the normal range of PCWP is 5 to 12 mm Hg for individuals without cardiac dysfunction, higher pressures (i.e., 15 to 18 mm Hg) are often necessary in patients with heart failure in order to optimize CI. Generally, the PCWP can be lowered to 15 to 18 mm Hg with relatively little decrease in cardiac output because the Frank-Starling curve is flatter at higher PCWP values in patients with heart failure (depicted in Figure 5-3). Cardiac output also declines when the PCWP desired in a heart failure patient (i.e., PCWP 15 to 18 mm Hg) is exceeded. This phenomenon may explain why patients may experience enhanced diuresis and improved renal function when the PCWP range of 15 to 18 mm Hg is achieved in a heart failure patient with fluid overload. IV administration of agents that reduce preload (i.e., loop diuretics, nitroglycerin, or nesiritide) are the most appropriate acute therapy to achieve the therapeutic goal for patients in subset II. Despite a very rapid onset with diuretic therapy, the time required for significant improvement in oxygenation with IV loop diuretics may take several hours in select patients. Thus, IV venodilators such as nitroglycerin and nesiritide may be utilized for rapid venodilation, which can acutely aid in improving hypoxia (Fig. 5-2).9
Current guidelines recommend loop diuretics as first-line therapy for patients with fluid overload and that such agents typically be administered IV.10 The rate of diuresis should achieve a desirable volume status without causing a rapid reduction in intravascular volume, which may result in symptomatic hypotension or renal dysfunction. Electrolyte depletion should be monitored closely especially when high doses or combination diuretic therapy is utilized. In addition to sodium restriction (less than 2 g daily), supplemental oxygen should be administered as needed for hypoxemia. In patients with moderate hyponatremia (less than 130 mEq/L [130 mmol/L]), fluid restriction (less than 2 L daily) should be considered, and in patients with worsening or severe hyponatremia (less than 125 mEq/L [125 mmol/L]), stricter fluid restriction may be necessary.10 The arginine vasopressin (AVP) antagonists are a new class of agents indicated for the management of euvolemic or hypervolemic hyponatremia in a variety of disease states including heart failure.25 Currently available vasopressin antagonists are discussed in greater detail later in this chapter.
IV vasodilators may be added to diuretics for rapid symptom resolution, especially in patients with acute pulmonary edema or severe hypertension. Such therapy may also be considered in patients who fail to respond to aggressive treatment with diuretics. Vasodilators should be avoided in patients with symptomatic hypotension, and frequent blood pressure monitoring is necessary to ensure their safe use. In addition, these agents should not be used in patients with reduced left heart filling pressures. If symptomatic hypotension occurs with vasodilator therapy, the dose should be reduced or the agent discontinued. If patients fail to respond to the above therapies or experience worsening renal function, IV inotropic therapy should be considered.10
Subset III
Patients in hemodynamic subset III have a CI of less than 2.2 L/min/m2 but without an abnormal elevation in PCWP (Fig. 5-1). These patients usually present without evidence of congestion, but low cardiac output results in signs and symptoms of peripheral hypoperfusion (i.e., decreased urine output, weakness, peripheral vasoconstriction, weak pulses). The mortality rate of subset III patients is reportedly higher than that of patients without hypoperfusion.24Although the treatment goal is to alleviate signs and symptoms of hypoperfusion by increasing CI and perfusion to essential organs, therapy may differ based on initial presentation. If the PCWP is significantly below 15 mm Hg, IV fluids should be administered to provide a more optimal left ventricular filling pressure (i.e., 15 to 18 mm Hg), consequently improving CI (Fig. 5-2). Alternatively, diuretic therapy should be held and fluid restriction liberalized. When only mild left ventricular dysfunction is present, IV fluid administration may be all that is necessary to achieve a CI above 2.2 L/min/m2 (0.037 L/s/m2). However, many patients will have significant left ventricular dysfunction and depressed Frank-Starling relationship despite adequate filling pressures. In such patients, IV administration of positive inotropic agents (e.g., dobutamine, milrinone) and/or arterial vasodilators (e.g., nitroprusside or nesiritide) may be necessary to achieve an adequate CI (Fig. 5-2). Some positive inotropic medications also have arterial vasodilating activity (see specific drug classes that follow).
Current guidelines recommend IV inotropes for symptom relief or end-organ dysfunction in patients with left ventricular dysfunction and low cardiac output syndrome.10 Such therapy may be especially useful in patients with low systolic blood pressure (less than 90 mm Hg) or symptomatic hypotension in the setting of adequate filling pressures. As previously discussed (see Subset II), inotropic therapy may be considered in patients who do not tolerate or respond to IV vasodilators or in patients with worsening renal function. As with vasodilators, inotrope administration requires frequent blood pressure monitoring as well as continuous monitoring for arrhythmias. If arrhythmias occur, dose reduction or discontinuation of inotropic therapy should be performed. As with vasodilators, these agents should be avoided in patients with low left heart filling pressures. Given the potential risks associated with inotropic therapy, vasodilators should be considered prior to using inotropes.10
In general, inotropic therapy should not be used routinely in the ADHF population. Instead, they should be reserved for the purpose of increasing cardiac output in the specific patients described above. These agents may also be used to “bridge” patients to heart transplantation or a left ventricular assist device, or as palliative therapy to improve functional status and quality of life in patients who are not candidates for these definitive therapies.10
Subset IV
Patients with a CI of less than 2.2 L/min/m2 (0.037 L/s/m2) and a PCWP higher than 18 mm Hg are in hemodynamic subset IV (Fig. 5-1). This subset is characterized by the worst prognosis of the four and represents the most common hemodynamic profile for patients with end-stage heart failure. Given the severity of systolic failure, such patients cannot maintain an adequate CI despite elevated left ventricular filling pressure and increased myocardial fiber stretch. Patients in subset IV will present with signs and symptoms of both congestion and hypoperfusion. Treatment goals for these patients include the alleviation of signs and symptoms by increasing CI above 2.2 L/min/m2(0.037 L/s/m2) and reducing PCWP to 15 to 18 mm Hg while maintaining an adequate mean arterial pressure. As a consequence, therapy will involve a combination of agents used in Subsets II and III in order to achieve these goals (i.e., combination of diuretic plus positive inotrope). These targets may be difficult to achieve and often necessitate careful monitoring and individualization of drug therapy. Nitroprusside may be a particularly useful agent in this setting because of its mixed arterial-venous vasodilating effects. However, in the presence of significant hypotension and low mean arterial pressures, inotropic agents with vasopressor activity (e.g., dopamine) may be required initially to achieve an adequate end-organ perfusion pressure and can then be combined, if necessary, with diuretics and/or therapies to obtain the desired hemodynamic effects and clinical response (Fig. 5-2).
PHARMACOLOGIC THERAPY OF ACUTE DECOMPENSATED HEART FAILURE
Unfortunately, drug therapies utilized in the management of ADHF have not improved substantially in the last decade due primarily to a dearth of clinical trial data in this population. The agents used to treat patients with ADHF rarely, if ever, produce a single cardiovascular action. Even when intended for a specific purpose (e.g., positive inotropic effects), other cardiovascular effects (tachycardia, vasodilation, or vasoconstriction) may either add to the therapeutic effect of the drug, or cause adverse effects that negate or even outweigh its intended therapeutic benefit. How an individual patient will respond to an intervention is often difficult to anticipate. For this reason, hemodynamic monitoring is often useful, and many drugs are considered first-line therapy due in part to their short half-lives and ease of titration. The description of expected drug actions outlined below should be viewed as a general guide to the clinician and patients should be continually reassessed for desired therapeutic outcomes. Table 5-4 contains a summary of the expected hemodynamic effects of the various drugs discussed below.
TABLE 5-4 Usual Hemodynamic Effects of IV Agents Commonly Used for Treatment of Advanced or Decompensated Heart Failurea
Diuretics
IV loop diuretics, including furosemide, bumetanide, and torsemide, are used commonly in the management of ADHF, with furosemide being the most widely studied and used in this setting.26–29 Bolus administration of diuretics reduces preload within 5 to 15 minutes by functional venodilation and later (>20 minutes) via sodium and water excretion, thereby improving pulmonary congestion. However, an acute reduction in venous return may severely compromise effective preload in patients with significant diastolic dysfunction, intravascular depletion, or those in whom CI is significantly dependent on adequate filling pressure (i.e., preload-dependent). This reduction in preload may result in reflex elevation of renin, norepinephrine, and AVP and the expected consequences of arteriolar and coronary vasoconstriction, tachycardia, and increased myocardial oxygen consumption. Unlike arterial vasodilators and positive inotropic agents, diuretics do not cause an upward shift in the Frank–Starling curve or significantly increase CI in most patients (Table 5-4 and Fig. 5-3). In fact, excessive preload reduction, specifically diuresis to a PCWP of less than 15 mm Hg, can lead to a decline in cardiac output (Fig. 5-3). Furthermore, intravascular volume depletion may occur in the setting of rapid diuresis despite relative overload of total body fluid, and thus, daily diuresis goals must be highly individualized. Most patients tolerate a 2 L/day net negative diuresis. However, some end-stage patients, especially those who are malnourished due to early satiety, will only tolerate 1 L/day net negative diuresis. Thus, diuretics must be used judiciously to obtain the desired improvement in congestive symptoms while avoiding a reduction in cardiac output, symptomatic hypotension, or worsening renal function. Although counterintuitive, patients with excessive fluid overload may initially present with compromised cardiac output, which may improve with diuresis once PCWP approaches desired ranges. This concept was described earlier in the chapter (Fig. 5-3) and may explain why renal function occasionally improves in the setting of diuresis.
Diuretic Resistance
Occasionally, patients respond poorly to large doses of loop diuretics, a phenomenon known as diuretic resistance. Heart failure is the most common clinical setting in which diuretic resistance is observed and multiple retrospective analyses suggest that diuretics, especially aggressive administration, may be associated with dose-dependent increases in mortality.30 Several studies also suggest that high doses are associated with renal dysfunction in ADHF,29,31which only further exacerbates diuretic resistance. Thus, the need for increased exposure to diuretics in the setting of resistance is concerning.
The mechanisms responsible for diuretic resistance in patients with heart failure are thought to be both pharmacokinetic and pharmacodynamic.32 The oral bioavailability of furosemide is relatively normal in heart failure patients, but the rate of absorption is prolonged approximately twofold and peak concentrations are reduced by approximately 50%. Because loop diuretics have a sigmoidal-shaped concentration–response curve, prolonged absorption may result in concentrations that fail to reach the threshold necessary for producing effective diuresis. Resistance is also observed with IV administration, suggesting an equally important pharmacodynamic contribution to this phenomenon. The decreased responsiveness in patients with heart failure may be explained in part by the high concentrations of sodium reaching the distal tubule as a result of blocked sodium reabsorption in the loop of Henle. As a consequence, the distal tubule undergoes hypertrophy, which enhances its ability to reabsorb sodium. Additionally, neurohormonal activation, low cardiac output, reduced renal perfusion, and decreased drug delivery to the kidney may also contribute to resistance.
Several strategies may be employed to overcome diuretic resistance. Current guidelines support one of three pharmacologic options in patients who do not initially respond to diuretic therapy.10 First, higher doses of loop diuretics may be administered to achieve concentrations near the top of the concentration–response curve. Although higher doses produce greater diuresis, these effects are not associated with improved long-term outcomes and must be weighed against the risk of worsening renal function.33 A second approach for overcoming diuretic resistance is the use of a continuous IV infusion, although this strategy has produced mixed results in clinical trials. Initial studies of continuous-infusion furosemide suggest a greater natriuretic effect with no difference in metabolic adverse effects when compared to the same total daily dose given by IV bolus.28,34,35 In another comparison of 56 patients with decompensated heart failure, use of a continuous furosemide infusion was associated with greater total urine output and shorter length of stay compared to IV bolus therapy, although net urine output and mean weight loss were unchanged.36 In the largest investigation to date, 308 patients with decompensated heart failure were randomized to a four-way comparison of low- and high-dose furosemide administered as a continuous infusion or intermittent IV bolus every 12 hours; although differences were observed in the comparison of low and high-dose furosemide, no differences in relief of symptoms, urine output, weight loss, or long-term outcomes were observed when administration by continuous infusion or intermittent IV bolus were compared.33
A third strategy for overcoming diuretic resistance is to add a second diuretic with a different mechanism of action. Combining a loop diuretic with a distal tubule blocker such as oral metolazone, oral hydrochlorothiazide (HCTZ), or IV chlorothiazide can produce a synergistic diuretic effect. Inhibition of sodium reabsorption in the loop of Henle increases sodium delivery to (and reabsorption in) the distal convoluted tubule, which can be subsequently blocked by a thiazide-type diuretic. Thus, when thiazide-type diuretics are added to a loop diuretic, they inhibit more than the usual 5% to 8% of filtered sodium, resulting in synergistic natriuresis. The combination of a loop and thiazide diuretic should generally be reserved for hospitalized patients, as profound diuresis with severe electrolyte and volume depletion may occur. If used in the outpatient setting, very low doses or only occasional administration of a thiazide-type diuretic should be recommended. Patients should also receive close follow-up (e.g., weight, vital signs, serum potassium, dizziness) to avoid serious adverse events.
Nonpharmacologic strategies for managing diuretic resistance include additional sodium and fluid restriction (i.e., less than 1 g and less than 1 L per day, respectively) and ultrafiltration, a strategy discussed in further detail later in this chapter.
Poor response to diuretic therapy may also result from worsening renal perfusion in the setting of low cardiac output. Thus, the use of positive inotropes or arterial vasodilators may improve diuresis by improving central hemodynamics. However, given the adverse effects of inotropic therapy, this option is generally reserved for patients not responding to all other therapies or those with evidence of low cardiac output. Administration of low doses of dopamine (i.e., 2 to 5 mcg/kg/min) to enhance diuresis was once common practice, but evidence to support its use remains controversial, as most studies indicate minimal if any improvement in diuresis.37 In a recent investigation comparing a high-dose furosemide infusion (20 mg/h) to the combination of a low-dose furosemide infusion (5 mg/h) and a dopamine infusion at 5 mcg/kg/h, reduced rates of worsening renal function were observed in the combination group despite similar rates of diuresis; however, because the trial did not include a group randomized to low-dose furosemide alone, it is not clear that these differences can be attributed to the addition of dopamine.38Additionally, at an infusion rate of 5 mcg/kg/min, dopamine exerts positive inotropic effects, thus it may not provide any advantages over a traditional inotrope when used in this setting.
Positive Inotropic Agents
The two positive inotropic agents currently approved for the management of ADHF are dobutamine and milrinone.39,40 Although both drugs increase intracellular concentrations of cyclic adenosine monophosphate (cAMP), the two do so by slightly different mechanisms. Dobutamine activates adenylate cyclase through direct stimulation of β-adrenergic receptors, thus catalyzing the conversion of adenosine triphosphate to cAMP, while milrinone reduces degradation of cAMP by inhibiting phosphodiesterase. Increased intracellular cAMP enhances phospholipase (and subsequently phosphorylase) activity, increasing the rate and extent of calcium influx during systole and enhancing contractility. Additionally, cAMP enhances reuptake of calcium by the sarcoplasmic reticulum during diastole, improving active relaxation.
Digoxin has a limited role in hemodynamically unstable patients due to its limited inotropic effect. In patients who take digoxin as chronic therapy, discontinuation or dose-adjustment during an acute decompensation is generally unnecessary unless changes in renal function increase the risk of toxicity. As discussed previously in this chapter, discontinuation should be discouraged given the potential for digoxin withdrawal unless there is a concern for toxicity.20,21
Differences in the pharmacologic effects of dobutamine and milrinone may confer advantages or disadvantages in a given patient. Therefore, clinical considerations for their use in the management of ADHF will be reviewed in the sections to follow.
Dobutamine
The receptor activities of dobutamine and other adrenergic agonists are summarized in Table 5-5. Dobutamine, a synthetic catecholamine, is a β1- and β2-receptor agonist with some α1-agonist effects. Unlike dopamine, dobutamine does not result in the release of norephinephrine from nerve terminals. Consequently, the positive inotropic effects of dobutamine are attributed to its effects on β1-receptors. Stimulation of cardiac β1-receptors by dobutamine does not generally produce a significant change in heart rate, thus explaining its more modest chronotropic effects compared with dopamine. Modest peripheral β2-receptor-mediated vasodilation tends to offset minor α1-receptor-mediated vasoconstriction with dobutamine. In addition, the increase in cardiac output often results in a reflexive decline in systemic vascular resistance. The net hemodynamic effect of dobutamine is usually vasodilation, which results from its effects on adrenergic receptors as well as reflex-mediated actions in vascular tissue.
TABLE 5-5 Relative Effects of Adrenergic Drugs on Receptors
The effects of dobutamine are observed within minutes but its peak effects may take up to 10 minutes to occur given an elimination half-life of 2 minutes. Initial doses of 2.5 to 5 mcg/kg/min may be increased progressively to 20 mcg/kg/min based on clinical and hemodynamic responses. Cardiac index is increased due to inotropic stimulation, arterial vasodilation, and a variable increase in heart rate. Because of offsetting changes in arteriolar resistance and CI, dobutamine usually causes relatively little change in mean arterial pressure, unlike the more consistent increases observed with dopamine. The vasodilating action of dobutamine usually reduces PCWP, making it particularly useful in the presence of low CI and an elevated left ventricular filling pressure; conversely, these effects may be detrimental in the presence of a reduced filling pressure. Although its impact on heart rate is variable, the major adverse effects of dobutamine are tachycardia and ventricular arrhythmias. Potentially detrimental increases in oxygen consumption have also been observed. While concerns exist regarding the attenuation of dobutamine’s effects during prolonged administration, some effect is likely retained, requiring that the dose of dobutamine be slowly tapered rather than abruptly discontinued.
Milrinone
Milrinone is a bipyridine derivative that inhibits phosphodiesterase III, an enzyme responsible for the breakdown of cAMP to AMP. Milrinone has supplanted the use of its prototype amrinone due to less frequent occurrence of thrombocytopenia. Because both positive inotropic and vasodilating effects contribute to its therapeutic effects in ADHF, milrinone is often referred to as an inodilator. The relative balance of these pharmacologic effects may vary with dose and underlying cardiovascular pathology.
During IV administration, milrinone produces an increase in stroke volume (and, therefore, cardiac output) with minimal change in heart rate (Table 5-4). Despite an increase in CI, mean arterial pressure may remain constant due to a concomitant decrease in arteriolar resistance. However, the vasodilating effects of milrinone may predominate, leading to a decrease in blood pressure and reflex tachycardia. Like dobutamine, milrinone lowers PCWP by venodilation and thus is particularly useful in patients with a low CI and an elevated left ventricular filling pressure. Such a reduction in preload, however, can be hazardous for patients without excessive filling pressure (especially those with subset III heart failure), thus blunting the improvement in cardiac output produced by the positive inotropic and arterial dilating actions of milrinone. Furthermore, milrinone should be used cautiously in severely hypotensive patients because it does not increase, and may even decrease, arterial blood pressure. Comparisons between dobutamine and milrinone indicate that the two agents generally produce similar hemodynamic effects, although dobutamine is usually associated with more pronounced increases in heart rate.
Milrinone has a longer elimination half-life than other vasoactive agents. In healthy subjects, the half-life of milrinone is about 1 hour but may be as long as 3 hours in patients with ADHF. The long elimination half-life of milrinone presents several disadvantages in this patient population, including the need for a loading dose in order to obtain a prompt initial response, the inability to perform minute-to-minute titrations based on hemodynamic changes, and persistence of adverse effects (e.g., arrhythmias or hypotension) following drug discontinuation. The usual loading dose for milrinone is 50 mcg/kg administered over 10 minutes, although this practice is uncommon due to an increased risk of hypotension. Most patients are started on a maintenance infusion of 0.1 to 0.3 mcg/kg/min (up to 0.75 mcg/kg/min), although lower initial doses may be considered. Milrinone is excreted unchanged in the urine, and thus, its infusion rate should be decreased by 50% to 70% in patients with significant renal impairment.
The most notable adverse effects associated with milrinone are arrhythmia, hypotension, and thrombocytopenia. While the incidence of thrombocytopenia with milrinone is rare, patients should still have platelet counts measured before and during therapy.
The combination of dobutamine and milrinone is likely to produce additive effects on CI and PCWP, suggesting this regimen as an option in patients who have dose-limiting adverse effects with either drug class. However, whether this combination provides a therapeutic advantage over the combined use of a positive inotrope and a traditional vasodilator (e.g., nitroprusside) is unclear.
Although not supported by evidence from clinical trials, many patients without signs or symptoms of hypoperfusion receive inotropic therapy in an effort to improve hemodynamics and thus shorten length of hospitalization and improve clinical outcomes. In one randomized trial designed to evaluate this strategy, no difference in length of stay was observed when 949 patients with ADHF were randomized to either a 48-hour infusion of milrinone or placebo.8 Adverse events were more common in the milrinone group, including sustained hypotension requiring intervention (10.7% vs. 3.2%; P < 0.001) and new onset of atrial fibrillation or flutter (4.6% vs. 1.5%; P = 0.004).
Recently, data from the ADHERE Registry (n = 15,230) has been used to compare in-hospital mortality among patients receiving IV nitroglycerin, nesiritide, milrinone, or dobutamine.41 After adjusting for baseline parameters known to predict in-hospital mortality, both dobutamine- and milrinone-treated patients experienced higher in-hospital mortality compared to those receiving either nitroglycerin or nesiritide (P < 0.005). In-hospital mortality was higher among patients receiving dobutamine compared to milrinone (P = 0.027), and no difference in in-hospital mortality was observed between nitroglycerin- and nesiritide-treated patients (P = 0.58).
Results from these studies add to the growing concern regarding the use of inotropic drugs in patients with ADHF and strongly suggest that they not be routinely used for the treatment of heart failure exacerbations. However, clinicians should be aware that inotropic therapy may be needed in select patients, such as those with low cardiac output states, end-organ hypoperfusion, or cardiogenic shock.10Dobutamine should be considered when a significant decrease in mean arterial pressure might further compromise hemodynamic function, as this effect is more common with the initiation of milrinone. Selection of an inotropic drug should also take into account whether patients are receiving chronic β-blocker therapy and whether a β1-selective agent (e.g., metoprolol succinate) or mixed α,β-blocking agent (e.g., carvedilol) is used. Generally, milrinone should be considered for patients who are receiving chronic β-blocker therapy because its inotropic effects do not involve stimulation of β-receptors. Continued β-blocker therapy may even augment the hemodynamic effects of milrinone, a phenomenon observed in studies with the structurally similar phosphodiesterase inhibitor enoximone.42 The hemodynamic effects of dobutamine may persist in the presence of β1-selective agents as a result of β-receptor upregulation or selective activation of β2-receptors by dobutamine. However, these effects are not observed in the presence of carvedilol, which may inhibit the hemodynamic benefits of dobutamine entirely.42
In some patients, dose reduction or discontinuation of positive inotropic therapy results in acute decompensation, requiring the placement of an indwelling IV catheter for continuous outpatient therapy. This approach may be used to “bridge” patients awaiting cardiac transplantation or left ventricular assist device placement, or to facilitate the discharge of patients who are not transplant candidates but who cannot be weaned from inotrope therapy. In this latter group, the use of outpatient intropic therapy is palliative and should only be considered after multiple unsuccessful attempts to maximize oral therapy and discontinue IV inotrope therapy. Although this strategy may be effective for symptom palliation, the risk of mortality is likely increased. In contrast, the use of regularly scheduled intermittent inotropic infusions is not recommended in current guidelines.10
Dopamine
Although dopamine should generally be avoided in the treatment of ADHF, a clinical scenario where its pharmacologic actions may be preferable to dobutamine or milrinone is in patients with marked systemic hypotension or cardiogenic shock in the face of elevated ventricular filling pressures, where dopamine in doses greater than 5 mcg/kg/min may be necessary to raise central aortic pressure. Although this strategy is common in clinical practice, minimal data exist to support its use.
Dopamine is an endogenous precursor of norepinephrine and exerts its effects by directly stimulating adrenergic receptors as well as causing release of norepinephrine from adrenergic nerve terminals. Dopamine produces dose-dependent hemodynamic effects as a result of its relative affinity for α1-, β1-, β2-, and D1- (vascular dopaminergic) receptors (see Table 5-4).
The positive inotropic effects of dopamine are mediated primarily by β1-receptors and become more prominent at doses of 2 to 5 mcg/kg/min. Cardiac index is increased because of an increase in stroke volume and a variable increase in heart rate, which is also partially dose-dependent. Minimal changes in systemic vascular resistance occur, presumably because neither vasodilation (D1- and β2-receptor-mediated) nor vasoconstriction (α1-receptor-mediated) predominates. However, at doses between 5 and 10 mcg/kg/min, chronotropic and α1-receptor-mediated vasoconstricting effects become more prominent. Mean arterial pressure is usually raised as a result of increases in both CI and systemic vascular resistance (Table 5-4). The vasoconstricting effects of higher doses may limit improvements in CI by increasing afterload and PCWP, thus complicating the management of patients with preexisting high afterload. In such patients, alternative agents (e.g., dobutamine, milrinone) or the addition of diuretics and/or vasodilators may be necessary.
Dopamine, particularly at higher doses, may also alter several parameters that increase myocardial oxygen demand (e.g., increased heart rate, contractility, and systolic pressure) and potentially decrease myocardial blood flow (e.g., coronary vasoconstriction and increased wall tension), which may worsen ischemia in patients with coronary artery disease. As with dobutamine and milrinone, arrhythmogenesis is also more common at higher dopamine doses.
Vasodilators
Activation of the sympathetic nervous system, renin–angiotensin–aldosterone system, and other neurohormonal mediators are characteristic features of both acute and chronic heart failure.29,43 Peripheral vasoconstriction and increased systemic vascular resistance often results, leading to a severe decline in stroke volume and thus cardiac output (Fig. 5-4).
FIGURE 5-4 Relationship between stroke volume and systemic vascular resistance. In an individual with normal left ventricular function, increasing systemic vascular resistance has little effect on stroke volume. As the extent of left ventricular dysfunction increases, the negative, inverse relationship between stroke volume and systemic vascular resistance becomes more important. Cardiac index is expressed in conventional units of mL/min/m2, and can be converted to SI units of mL/s/m2 by multiplying by 0.0167.
Vasodilators are commonly classified by their most prominent site of action (i.e., arterial or venous circulation). Arterial vasodilators act as impedance-reducing agents, reducing afterload and causing a reflexive increase in cardiac output. Venodilators act as preload reducers by increasing venous capacitance, thus reducing symptoms of pulmonary congestion in patients with high cardiac filling pressures. Mixed vasodilators act on both resistance and capacitance vessels, reducing congestive symptoms while increasing cardiac output. The most commonly used IV vasodilators in decompensated heart failure are nitroprusside, nitroglycerin, and nesiritide.
Nitroprusside
Sodium nitroprusside increases synthesis of nitric oxide in vascular smooth muscle, resulting in balanced arterial and venous vasodilation. As a result, nitroprusside increases CI and decreases venous pressure to a degree similar to dobutamine and milrinone, despite having no direct inotropic activity (Table 5-4); however, greater decreases in PCWP, systemic vascular resistance, and blood pressure are generally observed. Mean arterial pressure may remain fairly constant but often decreases depending on the relative increase in cardiac output and reduction in arteriolar tone. Hypotension is an important dose-limiting effect of nitroprusside; thus, it is used primarily in patients with significantly elevated systemic vascular resistance and often requires invasive hemodynamic monitoring.
Patients with normal left ventricular function do not experience an increase in stroke volume when systemic vascular resistance falls because the normal ventricle is fairly insensitive to small changes in afterload. Consequently, these patients may experience a significant decrease in blood pressure in response to arterial vasodilators. These differences explain why nitroprusside is a potent antihypertensive agent in patients without heart failure but causes less hypotension and reflex tachycardia in the presence of left ventricular dysfunction. Nonetheless, even a modest increase in heart rate can have adverse consequences in patients with underlying ischemic heart disease and/or resting tachycardia, thus necessitating close monitoring during therapy.
Nitroprusside is an effective strategy for the short-term management of patients with severe heart failure across a variety of settings (e.g., acute MI, valvular regurgitation, after coronary bypass surgery, decompensated chronic heart failure). Generally, nitroprusside does not worsen, and may even improve, the balance between myocardial oxygen demand and supply by lowering both left ventricular wall tension (thus reducing oxygen demand) and end-diastolic pressure (thereby increasing subendocardial blood flow). However, an excessive decrease in systemic arterial pressure may reduce coronary perfusion and worsen ischemia, leading to an increased risk of coronary steal.
Nitroprusside has a rapid onset of action but its effects last less than 10 minutes, necessitating its administration by continuous IV infusion. However, this method of administration allows precise dose-titration based on clinical and hemodynamic response. As with other vasodilators used in heart failure, nitroprusside should be initiated at low doses (0.1 to 0.2 mcg/kg/min) to avoid excessive hypotension and increased by small increments (0.1 to 0.2 mcg/kg/min) every 5 to 10 minutes as needed and tolerated. Effective doses usually range from 0.5 to 3 mcg/kg/min. A rebound phenomenon, which may be due to reflex neurohormonal activation during nitroprusside therapy, has been reported following abrupt withdrawal in patients with heart failure. Therefore, nitroprusside should be tapered slowly when transitioning patients to oral therapies. If renal perfusion pressure is compromised by nitroprusside administration, salt and water retention may contribute to volume expansion and tachyphylaxis, although this is typically only observed in patients with chronic hypertension, baseline azotemia, or when augmentation of cardiac output during therapy is minimal. Additionally, nitroprusside can cause cyanide and thiocyanate toxicity, but these effects are unlikely when doses less than 3 mcg/kg/min are administered for less than 3 days, except in patients with significant renal impairment (i.e., serum creatinine concentration greater than 3 mg/dL [265 μmol/L]). Nitroprusside should be avoided in the presence of elevated intracranial pressure because it may worsen cerebral edema in this setting. Given the potent pulmonary vasodilatory effects of nitroprusside as well as its short half-life, this agent is frequently used to determine reversibility of pulmonary hypertension in patients being evaluated for heart transplantation.
Unfortunately, no prospective randomized controlled trials have evaluated the use of nitroprusside in patients with ADHF. However, in one of the many retrospective studies in this population, patients with a reduced CI (i.e., less than or equal to 2 L/min/m2 [0.033 L/s/m2]) treated with nitroprusside (n = 78) experienced a reduction in all-cause mortality (P = 0.005) compared to patients who did not receive nitroprusside (n = 97). At baseline, patients receiving nitroprusside tended to have higher MAP, increased intracardiac filling pressures, and lower CI, but the observed improvements in mortality remained even after including only those patients who had initial MAP ≤85 mm Hg (P = 0.0001).44
Nitroglycerin
IV nitroglycerin is often the preferred agent for preload reduction in patients with ADHF, especially those with evidence of pulmonary congestion. Because of its short half-life, IV nitroglycerin is administered by continuous infusion. Its major hemodynamic effects are reductions in preload and PCWP via functional venodilation and mild arterial vasodilation that is particularly evident in patients with heart failure and elevated systemic vascular resistance (SVR) or when given in doses approaching 200 mcg/min (Table 5-4). In higher doses, nitroglycerin displays potent coronary vasodilating properties and thus beneficial effects on myocardial oxygen demand and supply, making it the vasodilator of choice for patients with severe heart failure and ischemic heart disease.
Nitroglycerin should be initiated at a dose of 5 to 10 mcg/min (0.1 mcg/kg/min) and increased every 5 to 10 minutes as necessary and tolerated. Hypotension and an excessive decrease in PCWP are important dose-limiting side effects. Maintenance doses usually vary from 35 to 200 mcg/min (0.5 to 3 mcg/kg/min). While tolerance to the hemodynamic effects of nitroglycerin may develop over 12 to 72 hours of continuous administration, some patients experience a sustained response. Like nitroprusside, nitroglycerin should not be used in the presence of elevated intracranial pressure because it may worsen cerebral edema in this setting.
In contrast to nitroprusside, one prospective randomized controlled trial has evaluated nitroglycerin in patients with ADHF. This study compared nitroglycerin to placebo as well as nesiritide and will be discussed in the following section.9
Nesiritide
Nesiritide is a recombinant form of BNP, which is secreted by the ventricular myocardium in response to volume overload. Exogenous administration of nesiritide mimics the vasodilatory and natriuretic actions of BNP by stimulating natriuretic peptide receptor A, which leads to increased levels of cGMP in target tissues. Nesiritide produces dose-dependent venous and arterial vasodilation; increases cardiac output, natriuresis, and diuresis; and decreases cardiac filling pressures and activation of the sympathetic nervous system and renin-angiotensin-aldosterone system. In contrast to nitroglycerin or dobutamine, tolerance does not develop to the pharmacologic actions of nesiritide. It also does not affect cAMP or β-receptors, mechanisms that are thought to contribute to the myocardial toxicity associated with the positive inotropic agents, including their proarrhythmic effects. Nesiritide is eliminated by several pathways including natriuretic peptide receptor C located on target tissues, proteolytic cleavage by neutral endopeptidase, and renal filtration. At 18 minutes, its elimination half-life is considerably longer than that of other IV vasoactive agents.
The precise role of nesiritide in the pharmacotherapy of ADHF remains controversial. Some of this controversy centers on the marginal lack of improvement in clinical outcomes with nesiritide compared to other IV vasodilators as well as its significantly greater costs (∼$450 for a 24-hour nesiritide infusion compared to $10 to $15 for nitroglycerin). In a randomized, double-blind trial comparing nesiritide to nitroglycerin or placebo in patients with ADHF and dyspnea, nesiritide improved the incidence of dyspnea at 3 hours when compared to placebo but failed to demonstrate a significant difference compared to nitroglycerin.9 In the subset of patients who received PA catheterization (permitted at the discretion of the investigators), nesiritide reduced PCWP at 3 hours when compared to both placebo and nitroglycerin. Two meta-analyses suggested an increased risk of negative outcomes with nesiritide including an increased risk of worsening renal function and an increased risk in mortality.45–47 In a trial designed to address these concerns, 7,141 patients hospitalized for ADHF were randomized to receive nesiritide at 0.01 μg/kg/min (with an optional 2 μg/kg IV bolus) or placebo for up to 7 days. Nesiritide demonstrated no difference in mortality and was not associated with worsening renal function as demonstrated in previous meta-analyses. Rehospitalization for heart failure at 30 days was also not affected by the use of nesiritide, nor was patient self-assessment of dyspnea symptoms after 6 hours and 24 hours of treatment.33 The results of this study only further emphasize the limited conclusions that can be made from meta-analyses as well as the need for large outcome-driven clinical trials in patients with ADHF.
Vasopressin Receptor Antagonists
Physiologic fluid balance depends on relative concentrations of sodium and water. An abnormally low sodium concentration, or hyponatremia, is commonly defined as less than 125 mEq/L (125 mmol/L) and can be classified as hypovolemic, euvolemic (urine sodium less than 30 mEq/L [30 mmol/L]), or hypervolemic (urine sodium greater than 30 mEq/L [30 mmol/L]) in nature. Diuretic administration may result in hypovolemic hyponatremia, excessive water consumption may result in euvolemic hyponatremia, and heart failure may be associated with hypervolemic hyponatremia. Other causes of hyponatremia include syndrome of inappropriate diuretic hormone (SIADH), cirrhosis with ascites, and medications.48
Hyponatremia is often characterized by inappropriately elevated concentrations of AVP, or antidiuretic hormone. In the setting of heart failure, reduced cardiac output leads to excess stimulation of arterial baroreceptors, which in turn enhances AVP secretion and consequently, net water retention. While the prevalence of hyponatremia in patients with heart failure varies by definition, as many as one in five patients hospitalized for acute heart failure presents with serum sodium concentrations less than 136 mEq/L (136 mmol/L).49 Furthermore, the presence of hyponatremia has been associated with increased mortality in this population.50
While many cases of hyponatremia are mild, asymptomatic, and self-limited, prompt diagnosis and management is critical for the less common but life-threatening presentation, which may include lethargy, confusion, respiratory arrest, cerebral edema, seizures, coma, or death. Treatment is specific to the underlying etiology, as well as duration and severity of symptoms. Strategies for managing hyponatremia include removal of the underlying cause, fluid restriction, isotonic or hypertonic saline administration, or administration of diuretics, vasopressin antagonists, or other therapies. Importantly, while neurological sequalae may occur if treatment is not initiated promptly, overly rapid correction of hyponatremia (greater than 12 mEq/L [12 mmol/L] per 24 hours) may be just as detrimental.51
The two currently available vasopressin receptor antagonists, tolvaptan and conivaptan, inhibit one or two AVP receptors, V1A or V2.52 Stimulation of V1A receptors, which are present in vascular smooth muscle and myocardium, results in vasoconstriction as well as myocyte hypertrophy, coronary vasoconstriction, and positive inotropic effects. V2 receptors are located in the renal tubules where they regulate water reabsorption. Tolvaptan selectively binds to and inhibits the V2 receptor, whereas conivaptan nonselectively inhibits both V1A and V2 receptors. Tolvaptan is orally bioavailable and indicated for the management of hypervolemic and euvolemic hyponatremia in patients with SIADH, cirrhosis, or heart failure. Tolvaptan is typically initiated at 15 mg daily and then titrated to 30 mg or 60 mg as needed for resolution of hyponatremia. Importantly, tolvaptan is a substrate of cytochrome P450 3A4 and is contraindicated with potent inhibitors of this enzyme. Conivaptan is an IV agent indicated for hypervolemic and euvolemic hyponatremia resulting from a variety of causes; however, because it is not indicated in patients with heart failure, conivaptan will not be discussed in further detail here. Patients receiving vasopressin antagonists must be monitored closely to avoid an overly rapid rise in serum sodium, which may result in hypotension or hypovolemia, requiring that therapy be discontinued. Therapy may be restarted at a lower dose if hyponatremia recurs or persists and/or adverse effects resolve.53
The role of vasopressin antagonists in the long-term management of heart failure remains unclear at this time. In two trials of patients with euvolemic or hypervolemic hyponatremia (one-third of whom had heart failure as the underlying etiology of hyponatermia), tolvaptan effectively increased serum sodium at 4 and 30 days, although hyponatremia recurred in the week following discontinuation.54 In a larger trial comprised entirely of hospitalized patients with NYHA class III to IV heart failure, tolvaptan was again associated with significant improvement in hyponatremia compared to placebo.55,56 Additionally, patients receiving tolvaptan experienced an improvement in diuresis and symptoms of congestion. Unfortunately, the study failed to demonstrate an improvement in global clinical status at discharge or a reduction in 2-year all-cause mortality, cardiovascular mortality, or heart failure rehospitalization.
Overall, tolvaptan is well tolerated; common side effects include dry mouth, thirst, urinary frequency, constipation, and hyperglycemia. While tolvaptan is orally available, therapy in clinical trials was initiated in the inpatient setting, where serum sodium and volume status could be closely monitored. Because of the adverse consequences of rapid changes in serum sodium concentrations or fluid balance, caution should be exerted when initiating therapy.
MECHANICAL CIRCULATORY SUPPORT
Intraaortic Balloon Pump
The intraaortic balloon pump (IABP) is a type of mechanical circulatory assistance device occasionally employed in patients with advanced heart failure who do not respond adequately to drug therapy, such as those with intractable myocardial ischemia or cardiogenic shock.57 The IABP consists of a polyethylene balloon mounted on a catheter that is usually inserted percutaneously into the femoral artery and advanced into the descending thoracic aorta. During counterpulsation, the balloon is synchronized with the ECG so that it inflates during diastole and displaces blood to the proximal aorta, thus increasing diastolic pressure and coronary perfusion. The balloon deflates just prior to the opening of the aortic valve during systole, which causes a sudden “vacuum-like” decrease in aortic pressure, allowing the left ventricle to pump against reduced arterial impedance. IABP support results in increased CI, coronary artery perfusion, and myocardial oxygen supply accompanied by decreased myocardial oxygen demand. Thus, it may be particularly useful for the short-term support of patients with myocardial ischemia complicated by cardiogenic shock, although it has not been shown to improve mortality in this setting.58 The IABP is also used in hemodynamically unstable patients who are unresponsive to inotropic therapy, where it may serve as a bridge to a surgical device or transplantation. IV vasodilators and inotropic agents are generally used in conjunction with the IABP to maximize its hemodynamic and clinical benefits.
Ventricular Assist Devices
Ventricular assist devices (VAD) provide mechanical circulatory support by assisting and, in some cases, replacing the pumping functions of the right and/or left ventricles.59 A left ventricular assist device (LVAD) removes blood directly from the left ventricle or left atrium and pumps it to the aorta, while a right VAD removes blood directly from the right ventricle or right atrium and pumps it to the PA. An RVAD may be used alone or in conjunction with an LVAD; this latter configuration is known as a biventricular assist device (BiVAD).
A number of VADs are currently available or under investigation. These devices may be used in the short term (days to weeks) for temporary stabilization while a patient awaits an intervention to correct the underlying cause of cardiac dysfunction, or they may be surgically implanted for the long term (months to years) as a bridge to heart transplantation. More recently, permanent device implantation (known as “destination therapy”) has become an option for patients who are not heart transplant candidates. While an RVAD (used alone or in combination with an LVAD) is primarily reserved for acute hemodynamic support, an LVAD may be considered for both short- and long-term use.
Short-term VAD use is indicated in patients requiring acute hemodynamic support during high-risk invasive procedures (e.g., percutaneous coronary intervention, coronary artery bypass graft surgery, valve repair or replacement), postoperative cardiac dysfunction, or cardiogenic shock, often in the setting of cardiac surgery. Several device types may be employed in the short-term setting, including implantable, extracorporeal (e.g., AB5000, Abiomed, Danvers, MA), and percutaneous models (e.g., Impella, Abiomed, Danvers, MA).
Intermediate-term and long-term devices may serve as a bridge to heart transplantation or in the case of the latter type, destination therapy for patients who are not transplant candidates. In one of the first pivotal trials assessing LVAD implantation, 129 patients who were ineligible for heart transplantation were randomized to the HeartMate XVE (Thoratec Corp., Pleasanton, CA) or optimal medical therapy. Although overall survival was low in both groups, LVAD patients experienced improved 1- and 2-year survival (52% vs. 25% and 23% vs. 8%, respectively, P = 0.009).60 In a trial evaluating the Novacor LVAD (WorldHeart, Ottawa, Canada) in an inotrope-dependent population, 1-year survival was improved in the LVAD arm (21% vs. 11% in medically treated patients, P = 0.02), but overall outcomes were inferior to those observed with the HeartMate XVE. Notably, some patients in the trial evaluating the Novacor device were more critically ill and would have been considered too high risk for the HeartMate XVE.61 While previous devices employed a pulsatile flow mechanism, newer-generation devices such as the HeartMate II LVAD (Thoratec Corp., Pleasanton, CA) utilize continuous axial flow, which allows them to be smaller in size and less subject to deterioration over time. When compared to the HeartMate XVE, the HeartMate II LVAD improved the rate of survival free from stroke and device failure at 2 years (46% vs. 11%, P < 0.001) and actuarial survival rates at 2 years (58% vs. 24%, P = 0.008).
Complications of LVAD implantation include bleeding, air embolism, right ventricular failure, as well as those associated with any major surgical procedure, including infection. In addition, the devices can cause hemolysis, thrombosis, renal and hepatic dysfunction, and arrhythmias. Device malfunction may also occur, but as LVAD technology advances, many complications are unrelated to the device itself, further emphasizing the role of appropriate candidate selection and identifying the optimal window for LVAD implantation.
Controversy exists regarding the cost of such procedures given the already significant economic impact of heart failure on the healthcare system.62 Although only a small number of patients have been studied, recent research suggests that prolonged unloading of the left ventricle with an LVAD in combination with drug therapy can produce sustained recovery in LV function and amelioration of symptoms.63Furthermore, more recent data suggest that patients referred for LVAD prior to the development of major complications of heart failure experience improved survival.64
For complete heart replacement therapy, total artificial heart systems continue to be investigated; however, embolic complications as well as the large size of the currently available systems limit their widespread use. Percutaneously inserted catheter-based LVADs are a more recent advancement. These small pumps may offer an advantage as they avoid the need for open-heart surgery; however, this technology is still in developmental stages.
Ultrafiltration
Renal impairment is common among patients with ADHF, and advanced forms may warrant the use of renal replacement therapy (e.g., hemodialysis). Ultrafiltration has emerged as another strategy for rapid fluid removal, where salt and water may be eliminated at rates of up to 500 mL/h. Ultrafiltration reduces PCWP and increases diuresis without adversely affecting hemodynamics (i.e., blood pressure, heart rate) or renal function, and is thought to be safer than diuretic therapy because fluid removal is isotonic. Potential candidates for ultrafiltration include patients demonstrating diuretic resistance, renal impairment following diuretic administration, or continued renal impairment despite inotropic therapy. Complications of ultrafiltration include those associated with central venous access (e.g., infection), rapid volume removal, and intravascular depletion, although electrolyte depletion is generally less significant compared to other treatment modalities.
Small studies suggest that ultrafiltration represents an effective strategy for fluid removal in heart failure patients and that early initiation prior to IV diuretics reduces hospital length of stay and readmission rates. In a study comparing early ultrafiltration to IV diuretics in patients with ADHF and evidence of fluid overload, ultrafiltration resulted in greater weight loss at 48 hours (5 kg vs. 3.1 kg) as well as net fluid loss (4.6 L vs. 3.3 L), although no differences in dyspnea scores were observed.65 Several additional endpoints were improved among patients in the ultrafiltration group, including the incidence and duration of rehospitalization and incidence of unscheduled office or emergency department visits at 90 days. Although these results are promising, larger studies are necessary to determine the role of ultrafiltration in the management of ADHF.
HEART TRANSPLANTATION
Orthotopic heart transplantation remains the optimal management strategy for patients with chronic, irreversible NYHA class IV heart failure, as 10-year survival rates approach 50% among well-selected transplant recipients.66Unfortunately, the shortage of acceptable donor hearts has led to long waiting times and many patients succumb to their disease prior to transplantation. Another significant percentage of patients are deemed ineligible for transplantation because of age, concurrent illnesses, psychosocial factors, or other reasons. The shortage of donor hearts has prompted the development of new surgical strategies, including ventricular aneurysm resection, mitral valve repair, and myocardial cell transplantation, which have resulted in variable degrees of symptomatic improvement. Further development of these and other techniques may offer additional options in patients who are not considered candidates for transplantation.
EVALUATION OF THERAPEUTIC OUTCOMES
Assessment of therapeutic outcomes in patients with ADHF can be separated into two general categories: initial improvement of physiologic parameters and safe discharge from the hospital following transition to chronic oral medications. Both goals are equally important because hemodynamic improvement alone is not associated with prolonged symptom improvement or enhanced survival.
Initial stabilization requires an adequate arterial oxygen saturation, CI, and blood pressure necessary to maintain end-organ perfusion. Functional end-organ perfusion may be assessed by the presence of an appropriate mental status, renal function sufficient to prevent metabolic complications, hepatic function adequate to maintain synthetic and excretory functions, stable heart rate and rhythm (i.e., predominately sinus rhythm, rate-stabilized atrial fibrillation or flutter, or paced rhythm), absence of ongoing myocardial ischemia, skeletal muscle and skin blood flow sufficient to prevent ischemic injury, and normal arterial pH (7.34 to 7.47) and serum lactate concentration. Although these goals are most often achieved with a CI greater than 2.2 L/min/m2 (0.037 L/s/m2), mean arterial blood pressure greater than 60 mm Hg, and PCWP greater than 15 mm Hg, these absolute values are highly variable and depend on chronicity of illness, efficacy of chronic compensatory mechanisms, previous chronic therapy, and concurrent illnesses.
Discharge from the hospital requires maintaining the preceding parameters in the absence of ongoing IV therapy, mechanical circulatory support, or positive-pressure ventilation. Some patients may achieve this goal with markedly lower blood pressure or higher filling pressure than previously suggested; hence numerical goals cannot always be substituted for clinical status. Nonpharmacologic strategies aimed at the precipitants of a heart failure exacerbation include permanent pacing, chronic resynchronization therapy (i.e., biventricular pacing) with or without an implantable cardioverter-defibrillator, coronary angioplasty or valvuloplasty, pericardial drainage, cardiac surgery (coronary bypass, valve replacement or reconstruction, closure of intracardiac shunts), or cardiac transplantation to achieve initial stabilization, definitive therapy, or both.
PREPARATION FOR HOSPITAL DISCHARGE
All factors contributing to a heart failure decompensation should be addressed prior to discharge. Patients should be near or at optimal fluid status and transitioned from IV to oral diuretic therapy. Other chronic drug therapy should be optimized and appropriate follow-up clinic appointments scheduled. Typically, patients should be seen in clinic within 7 to 10 days of discharge. Both patients and their families should also receive appropriate education (see details below). For patients with recurrent hospital admissions, additional discharge criteria should be considered (Table 5-6).10
TABLE 5-6 Discharge Criteria for Patients with HF
Patient education is essential in the discharge process and should involve input from a variety of disciplines, including dietitians, pharmacists, and other healthcare providers. Teaching should promote self-care by emphasizing specific positive and negative behaviors. By understanding key concepts of heart failure and its management, patient self-care should improve and future hospitalizations may be avoided.10
While all patients are likely to benefit from education, those with more severe symptoms (NYHA class III or IV) require the most comprehensive counseling. During the acute hospitalization, providers should educate on the most essential topics; this information should be reinforced and supplemented in the clinic setting within a couple of weeks after discharge. Recently hospitalized patients should also be considered for referral to a disease management program.
In end-stage disease, quality of life and prognosis should be discussed with patients and caregivers, and if possible, while the patient is still able to participate in the decision-making process. End-of-life care should be considered in patients with persistent symptoms at rest despite multiple attempts to optimize therapy, especially those with frequent hospitalizations, limited quality of life, dependence on intermittent or continuous IV therapy, or for those who might benefit from assist devices as destination therapy. In such cases, inactivation of an implantable cardioverter-defibrillator should be discussed and patients may be considered for a palliative care approach or hospice services.10As clinical status deteriorates and medical therapies become ineffective, healthcare providers should transition from focusing on mortality reduction to palliation of symptoms.67
PHARMACOECONOMIC CONSIDERATIONS
Heart failure imposes a tremendous economic burden on the healthcare system. Admission rates continue to grow and heart failure has become the most common reason for hospitalization among patients over the age of 65. Heart failure is also associated with unacceptably high readmission rates during the first 3 to 6 months after discharge. Current estimates of the costs of heart failure treatment in the United States approach $32 billion for 2013, with the greatest expense attributed to hospitalization. In addition, it is estimated that the total cost of HF will increase almost 120% to $70 billion by 2030.1 The prevalence of heart failure and its associated costs are expected to increase as the population ages, especially as a result of improved survival from ischemic heart disease. Consequently, approaches aimed at improving the quality and cost-effectiveness of care for these patients may have a significant impact on healthcare costs.
Disease management programs have recently emerged as a novel approach for coordinating the increasingly complex management of heart failure. These programs utilize several approaches, including heart failure specialty clinics and/or home-based interventions. Most programs are multidisciplinary in nature and may include physicians, advanced practice nurses, dieticians, and pharmacists. Shown to reduce mortality, hospitalizations, and healthcare costs68, this team-based approach allows providers to address a variety of issues, including optimization of drug and nondrug therapy; provide patient and family education, exercise and dietary advice, and intense follow-up by telephone or home visits; and monitoring and management of signs and symptoms of decompensation.
Pharmacists play an important role in the multidisciplinary management of heart failure and impact care in a number of ways, including optimization of doses of heart failure drug therapy, screening for drugs that exacerbate heart failure, monitoring for adverse drug effects and drug interactions, educating patients, and patient follow-up.69,70 Compared to conventional care, these interventions have been shown to reduce hospitalizations for heart failure and improve adherence to guideline-recommended therapy. Additionally, a recent study found that pharmacist intervention also improved medication adherence and reduced emergency department visits and hospitalizations in low-income patients with heart failure.71 Taken together, the results of these studies demonstrate the impact pharmacists can have on both patient outcomes and the cost-effectiveness of care.
FUTURE THERAPIES
Over the past decade, a number of large, international phase III development programs have failed to demonstrate a significant benefit in ADHF, including studies of the endothelin receptor antagonist tezosentan, calcium sensitizer levosimendan, vasopressin receptor antagonist tolvaptan, and adenosine A-1 receptor antagonist rolofylline. Potential explanations for the lack of positive findings include patient heterogeneity, limited understanding of underlying pathophysiology, improvements in background therapy, and limitations of study design including patient selection, timing and duration of intervention, and defined endpoints.72 A number of investigations are currently underway to address these shortcomings as well as identify new and novel treatment strategies for patients with ADHF. Three pharmacologic therapies currently being investigated in patients with ADHF include serelaxin, omecamtiv mecarbil, and aliskiren.
Serelaxin is a novel recombinant form of human relaxin 2, a hormone that modulates the cardiovascular response during pregnancy (e.g., vasodilation, augmented renal function) as well as other important hemodynamic and neurohormonal effects.73 A large randomized controlled trial is currently underway to assess the impact of serelaxin on shortness of breath and all-cause mortality in patients with ADHF and systolic blood pressure >125 mm Hg.74Preliminary results indicate a reduction in all-cause mortality among patients randomized to serelaxin compared to placebo.75
Omecamtiv mecarbil is a cardiac-specific activator of myosin, a motor protein responsible for cardiac contraction. Omecamtiv mecarbil activates myocardial ATPase, which improves energy utilization and enhances myosin cross-bridge formation and duration. It also increases the rate of phosphate release from myosin, thereby accelerating the rate-determining step of the cross-bridge cycle. As a result, omecamtiv mecarbil improves myocardial efficiency by increasing the duration of systolic ejection (and thus, stroke volume) without consuming additional energy or oxygen and without altering intracellular calcium levels.76 Although omecamtiv mecarbil improves cardiac performance in the short term, its long-term effects have yet to be studied. An investigation of its role in patients with ADHF and left ventricular dysfunction is currently underway.77,78
Aliskiren is a direct renin inhibitor with favorable neurohormonal and hemodynamic effects that may be beneficial in patients with both chronic heart failure and ADHF. Given the neurohormonal abnormalities often present in patients with ADHF, the addition of aliskiren to standard therapy may reduce postdischarge mortality and rehospitalization. A trial evaluating these endpoints among patients with ADHF is currently underway.
Other therapies currently being investigated in ADHF include: nitroxyl, a reduced form of nitric oxide with arterial and venodilatory properties as well as positive inotropic and lusitropic properties; cenderitide (CD-NP), a chimeric protein that causes cGMP-mediated venodilation and aldosterone blockade; cinaciguat, a novel vasodilator that activates soluble guanylyl cyclase, leading to increased cGMP and subsequent venous and arterial vasodilation as well as reduced cell proliferation; clevidipine, a novel calcium channel blocker that selectively dilates arteries with no significant effect on myocardial contractility; and istaroxime, which inhibits sodium–potassium ATP activity and stimulates sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a (SERCA2a), thereby increasing lusitropy and inotropy.79 Additional studies currently underway include investigations of novel biomarkers in determining diagnosis, prognosis, and optimal management of ADHF; renal optimization strategies such as low-dose nesiritide and low-dose dopamine; mechanical support devices; and various interdisciplinary models of care.
CLINICAL CONTROVERSIES
1. The optimal pharmacotherapy for patients with ADHF who are refractory to diuretic therapy has been clarified by investigations showing minimal to no difference between administration by IV bolus or continuous infusion. Higher doses (i.e., 2.5-times the previous oral dose) of IV diuretic are more effective than lower doses (i.e., equivalent to previous oral dose) but may also result in greater rates of renal dysfunction. The following controversies remain unaddressed by the current literature: the role of adding a diurectic with an alternative mechanism of action, which alternative diuretic should be added (e.g., metolazone, HCTZ, other), and the role of ultrafiltration.
2. The role of nesiritide in ADHF has also been clarified. After two meta-analyses suggested that its use was associated with worsening renal function and increased mortality, a recent investigation found that nesiritide neither improved nor worsened outcomes in ADHF. However, the efficacy and safety of other vasodilators have not been well established and the use of positive inotropes has been associated with poor outcomes.
3. Clinicians continue to struggle with avoiding cardiorenal syndrome while trying to manage ADHF patients. Novel therapies or therapeutic strategies to address cardiorenal syndrome continue to evolve. Evolving data regarding the role of LVADs as a bridge to transplantation or destination therapy provide further support for the use of these therapeutic modalities. Additional data are warranted to further define the most optimal candidates, timelines for implantation, and how to best minimize complications associated with these devices.
ABBREVIATIONS
REFERENCES
1. Go AS, Mozaffarian D, Roger VL, et al. Heart Disease and Stroke Statistics—2013 Update: A Report From the American Heart Association. Circulation 2013;127:e6–e245. doi: 10.1161/CIR.0b013e31828124ad.
2. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2012 update: A report from the American Heart Association. Circulation 2012;125(1):e2–e220. doi: 10.1161/CIR.0b013e31823ac046.
3. Mehra MR. Optimizing outcomes in the patient with acute decompensated heart failure. Am Heart J 2006;151(3):571–579.
4. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119(14):e391–479. doi: 10.1161/circulationaha.109.192065
5. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation 2005;112(12):e154–e235.
6. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119(14):1977–2016.
7. Felker GM, Adams KF Jr, Konstam MA, O’Connor CM, Gheorghiade M. The problem of decompensated heart failure: Nomenclature, classification, and risk stratification. Am Heart J 2003;145(2 Suppl):S18–S25.
8. Cuffe MS, Califf RM, Adams KF, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: A randomized controlled trial. JAMA 2002;287(12):1541–1547.
9. The VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: A randomized controlled trial. JAMA 2002;287(12):1531–1540.
10. Lindenfeld J, Albert NM, Boehmer JP, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail 2010;16(6):e1–e194. doi: 10.1016/j.cardfail.2010.04.004
11. Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: Current state and framework for future research. Circulation 2005;112(25):3958–3968.
12. Adams KFJr, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: Rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149(2):209–216.
13. Fonarow GC, Adams KF Jr, Abraham WT, Yancy CW, Boscardin WJ. Risk stratification for in-hospital mortality in acutely decompensated heart failure: Classification and regression tree analysis. JAMA 2005;293(5):572–580.
14. O’Connor CM, Abraham WT, Albert NM, et al. Predictors of mortality after discharge in patients hospitalized with heart failure: An analysis from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). Am Heart J 2008;156(4):662–673.
15. Nohria A, Mielniczuk LM, Stevenson LW. Evaluation and monitoring of patients with acute heart failure syndromes. Am J Cardiol 2005;96(6A):32G–40G.
16. Adams KF, Lindenfeld J, Arnold JMO, et al. HFSA 2006 Comprehensive Heart Failure Practice Guideline: Section 7: Heart failure in patients with left ventricular systolic dysfunction. J Card Fail 2006;12(1):e38–e57.
17. Maisel A, Mueller C, Adams K Jr, et al. State of the art: Using natriuretic peptide levels in clinical practice. Eur J Heart Fail 2008;10(9):824–839.
18. Fonarow GC, Abraham WT, Albert NM, et al. Influence of beta-blocker continuation or withdrawal on outcomes in patients hospitalized with heart failure: Findings from the OPTIMIZE-HF program. J Am Coll Cardiol 2008;52(3):190–199. doi: 10.1016/j.jacc.2008.03.048
19. Jondeau G, Neuder Y, Eicher JC, et al. B-CONVINCED: Beta-blocker continuation Vs. interruption in patients with congestive heart failure hospitalized for a decompensation episode. Eur Heart J 2009;30(18):2186–2192. doi: 10.1093/eurheartj/ehp323
20. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993;329(1):1–7. doi: 10.1056/nejm199307013290101
21. Uretsky B, Young JB, Shahidi FE, et al. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: Results of the PROVED trial. J Am Coll Cardiol 1993;22:955–962.
22. Nohria A, Lewis E, Stevenson LW. Medical management of advanced heart failure. JAMA 2002;287(5):628–640.
23. Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: The ESCAPE trial. JAMA 2005;294(13):1625–1633.
24. Forrester JS, Diamond G, Chatterjee K, Swan HJC. Medical therapy of acute myocardial infarction by application of hemodynamic subsets. N Engl J Med 1976;295:1356–1362.
25. Finley JJ 4th, Konstam MA, Udelson JE. Arginine vasopressin antagonists for the treatment of heart failure and hyponatremia. Circulation 2008;118(4):410–421.
26. Brater DC. Pharmacology of diuretics. Am J Med Sci 2000;319(1):38–50.
27. Brater DC. Diuretic therapy in congestive heart failure. CHF 2000;6:197–210.
28. Iyengar S, Abraham WT. Diuretics for the treatment of acute decompensated heart failure. Heart Fail Rev 2007;12(2):125–130.
29. Stough WG, O’Connor CM, Gheorghiade M. Overview of current noninodilator therapies for acute heart failure syndromes. Am J Cardiol 2005;96(6A):41G–46G.
30. Eshaghian S, Horwich TB, Fonarow GC. Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol 2006;97(12):1759–1764.
31. Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 2004;147(2):331–338.
32. Cleland JG, Coletta A, Witte K. Practical applications of intravenous diuretic therapy in decompensated heart failure. Am J Med 2006;119(12 Suppl 1):S26–36.
33. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364(9):797–805. doi: 10.1056/NEJMoa1005419
34. Adams KF, Lindenfeld J, Arnold JMO, et al. HFSA 2006 Comprehensive Heart Failure Practice Guideline: Section 12: Evaluation and management of patients with acute decompensated heart failure. J Card Fail 2006;12(1):e86–e103.
35. Dormans TP, van Meyel JJ, Gerlag PG, Tan Y, Russel FG, Smits P. Diuretic efficacy of high dose furosemide in severe heart failure: Bolus injection versus continuous infusion. J Am Coll Cardiol 1996;28(2):376–382.
36. Thomson MR, Nappi JM, Dunn SP, et al. Continuous versus intermittent infusion furosemide in acute decompensated heart failure. J Card Fail 2010;16(3):188–193.
37. Vargo DL, Brater DC, Rudy DW, Swan SK. Dopamine does not enhance furosemide-induced natriuresis in patients with congestive heart failure. J Am Soc Nephrol 1996;7(7):1032–1037.
38. Giamouzis G, Butler J, Starling RC, et al. Impact of dopamine infusion on renal function in hospitalized heart failure patients: Results of the dopamine in acute decompensated heart failure (DAD-HF) trial. J Card Fail 2010;16(12):922–930. doi: 10.1016/j.cardfail.2010.07.246
39. Bayram M, De Luca L, Massie MB, Gheorghiade M. Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes. Am J Cardiol 2005;96(6A):47G–58G.
40. Lehtonen LA, Antila S, Pentikainen PJ. Pharmacokinetics and pharmacodynamics of intravenous inotropic agents. Clin Pharmacokinet 2004;43(3):187–203.
41. Abraham WT, Adams KF, Fonarow GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 2005;46(1):57–64.
42. Metra M, Nodari S, D’Aloia A, et al. Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: A randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol. J Am Coll Cardiol 2002;40(7):1248–1258.
43. Dorsch MP, Rodgers JE. Nesiritide: Harmful or harmless? Pharmacotherapy 2006;26(10):1465–1478.
44. Mullens W, Abrahams Z, Francis GS, et al. Sodium nitroprusside for advanced low-output heart failure. J Am Coll Cardiol 2008;52(3):200–207. doi: 10.1016/j.jacc.2008.02.083
45. Aaronson KD, Sackner-Bernstein J. Risk of death associated with nesiritide in patients with acutely decompensated heart failure. JAMA 2006;296(12):1465–1466. doi: 10.1001/jama.296.12.1465
46. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: A pooled analysis of randomized controlled trials. JAMA 2005;293(15):1900–1905.
47. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111(12):1487–1491.
48. Reynolds RM, Padfield PL, Seckl JR. Disorders of sodium balance. BMJ 2006;332(7543):702–705.
49. Gheorghiade M, Gattis WA, O’Connor CM, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: A randomized controlled trial. JAMA 2004;291(16):1963–1971.
50. Lee WH, Packer M. Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation 1986;73(2):257–267.
51. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342(21):1581–1589.
52. Lee CR, Watkins ML, Patterson JH, et al. Vasopressin: A new target for the treatment of heart failure. Am Heart J 2003;146(1):9–18.
53. Tolvaptan (Samsca™) package insert. Rockville, MD: Otsuka America Pharmaceutical, Inc., May 2009.
54. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006;355(20):2099–2112.
55. Gheorghiade M, Konstam MA, Burnett JC Jr, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST Clinical Status Trials. JAMA 2007;297(12):1332–1343.
56. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA 2007;297(12):1319–1331.
57. Boehmer JP, Popjes E. Cardiac failure: Mechanical support strategies. Crit Care Med 2006;34(9 Suppl):S268–S277.
58. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012;367(14):1287–1296. doi: 10.1056/NEJMoa1208410
59. Lietz K, Miller LW. Destination therapy: Current results and future promise. Semin Thorac Cardiovasc Surg 2008;20(3):225–233.
60. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001;345(20):1435–1443.
61. Rogers JG, Butler J, Lansman SL, et al. Chronic mechanical circulatory support for inotrope-dependent heart failure patients who are not transplant candidates: Results of the INTREPID Trial. J Am Coll Cardiol 2007;50(8):741–747.
62. Russo MJ, Gelijns AC, Stevenson LW, et al. The cost of medical management in advanced heart failure during the final two years of life. J Card Fail 2008;14(8):651–658.
63. Birks EJ, Tansley PD, Hardy J, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med 2006;355(18):1873–1884.
64. Lietz K, Long JW, Kfoury AG, et al. Outcomes of left ventricular assist device implantation as destination therapy in the post-REMATCH era: Implications for patient selection. Circulation 2007;116(5):497–505.
65. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49(6):675–683.
66. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: Twenty-third official adult heart transplantation report—2006. J Heart Lung Transplant 2006;25(8):869–879.
67. Hauptman PJ, Havranek EP. Integrating palliative care into heart failure care. Arch Intern Med 2005;165(4):374–378.
68. Holland R, Battersby J, Harvey I, Lenaghan E, Smith J, Hay L. Systematic review of multidisciplinary interventions in heart failure. Heart 2005;91(7):899–906.
69. Gattis WA, Hasselblad V, Whellan DJ, O’Connor CM. Reduction in heart failure events by the addition of a clinical pharmacist to the heart failure management team. Arch Int Med 1999;159:1939–1945.
70. Whellan DJ, Gaulden L, Gattis WA, et al. The benefit of implementing a heart failure disease management program. Arch Intern Med 2001;161(18):2223–2228.
71. Murray MD, Young J, Hoke S, et al. Pharmacist intervention to improve medication adherence in heart failure. A randomized trial. Ann Intern Med 2007;146:714–725.
72. Felker GM, Pang PS, Adams KF, et al. Clinical trials of pharmacological therapies in acute heart failure syndromes: Lessons learned and directions forward. Circ Heart Fail 2010;3(2):314–325. doi: 10.1161/circheartfailure.109.893222
73. Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M. Relaxin: Review of biology and potential role in treating heart failure. Curr Heart Fail Rep 2010;7(2):75–82. doi: 10.1007/s11897-010-0010-z
74. Ponikowski P, Metra M, Teerlink JR, et al. Design of the RELAXin in acute heart failure study. Am Heart J 2012;163(2):149–155 e141. doi: 10.1016/j.ahj.2011.10.009
75. Teerlink JR, Metra M, Felker GM, et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): A multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet 2009;373(9673):1429–1439. doi: 10.1016/s0140-6736(09)60622-x
76. Malik FI, Hartman JJ, Elias KA, et al. Cardiac myosin activation: A potential therapeutic approach for systolic heart failure. Science 2011;331(6023):1439–1443. doi: 10.1126/science.1200113
77. Cleland JG, Teerlink JR, Senior R, et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: A double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 2011;378(9792):676–683. doi: 10.1016/s0140–6736(11)61126–4
78. Teerlink JR, Clarke CP, Saikali KG, et al. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: A first-in-man study. Lancet 2011;378(9792):667–675. doi: 10.1016/s0140-6736(11)61219-1
79. Majure DT, Teerlink JR. Update on the management of acute decompensated heart failure. Curr Treat Options Cardiovasc Med. 2011;13(6):570–585. doi: 10.1007/s11936-011-0149-2