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Management of Heart Failure Patients with Reduced Ejection Fraction
Additional content is available online at Elsevier eBooks for Practicing Clinicians
The epidemiology and clinical assessment of patients with heart failure (HF) is reviewed in Chapter 48 , whereas the following chapter will focus on the management of patients with a reduced ejection fraction, which is referred to as HFrEF . The diagnosis and management of patients with acute HF is discussed in Chapter 49 , and the management of patients with an HF with a preserved ejection fraction (HFpEF) is discussed in Chapter 51 .
Etiology
As shown in Table 50.1 , any condition that leads to an alteration in left ventricular (LV) structure or function can predispose a patient to developing HF. Although the etiology of HF in patients with HFrEF differs from that of patient with HFpEF (see Chapter 48 ), there is considerable overlap between the etiologies of these two conditions. In industrialized countries, coronary artery disease (CAD) is the predominant cause in etiology in men and women and is responsible for 60% to 75% of cases of HF. Hypertension contributes to the development of HF in a significant number of patients, including most patients with CAD. Both CAD and hypertension interact to augment the risk of HF. Rheumatic heart disease remains a major cause of HF in Africa and Asia, especially in the young. Hypertension is an important cause of HF in the African and African American population. Chagas disease is still a major cause of HF in South America. As developing nations undergo socioeconomic development, the epidemiology of HF is becoming similar to that of Western Europe and North America, with CAD emerging as the single most common cause of HF.
TABLE 50.1
Risk Factors for Cardiac Failure (Olmstead County)
From Dunlay SM, Weston SA, Jacobsen SJ, et al. Risk factors for heart failure: a population-based case-control study. Am J Med . 2009;122:1023–1028.
| Risk Factor | Odds Ratio (95% CI) | P Value | Population Attributable Risk (96 = 5% CI) | ||
|---|---|---|---|---|---|
| Overall | Women | Men | |||
| Coronary heart disease | 3.05 (2.36–3.95) | <.001 | 0.20 (0.16–0.24) | 0.16 (0.12–0.20) | 0.23 (0.16–0.30) |
| Hypertension | 1.44 (1.18–1.76) | <.001 | 0.20 (0.10–0.30) | 0.28 (0.14–0.42) | 0.13 (0.00–0.26) |
| Diabetes | 2.65 (1.98–3.54) | <.001 | 0.12 (0.09–0.15) | 0.10 (0.06–0.14) | 0.13 (0.08–0.18) |
| Obesity | 2.00 (1.57–2.55) | <.001 | 0.12 (0.08–0.16) | 0.12 (0.07–0.17) | 0.13 (0.07–0.19) |
| Ever smoker | 1.37 (1.13–1.68) | .002 | 0.14 (0.06–0.22) | 0.08 (0.00–0.15) | 0.22 (0.07–0.37) |
In 20% to 30% of the cases of HFrEF, the exact etiologic basis is not known. These patients are referred to as having dilated or idiopathic cardiomyopathy if the cause is unknown (see Chapter 52 ). Prior viral infection ( Chapter 55 ) or toxin exposure (e.g., alcohol [ Chapter 84 ] or use of chemotherapeutic agents [ Chapter 56, Chapter 57 ]) may also lead to a dilated cardiomyopathy. Although excessive alcohol consumption can promote cardiomyopathy, alcohol consumption per se is not associated with increased risk for HF, and alcohol may protect against the development of HF when consumed in moderation. It is also becoming increasingly clear that a large number of the cases of dilated cardiomyopathy are secondary to specific genetic defects, most notably those in the cytoskeleton (see Chapter 52 ). Most of the forms of familial dilated cardiomyopathy are inherited in an autosomal dominant fashion. Mutations of genes encoding cytoskeletal proteins (desmin, cardiac myosin, vinculin) and nuclear membrane proteins (lamin) have been identified thus far. Dilated cardiomyopathy is also associated with Duchenne, Becker, and limb girdle muscular dystrophies (see Chapter 100 ). Conditions that lead to a high cardiac output (e.g., arteriovenous fistula, anemia) are seldom responsible for the development of HF in a normal heart. However, in the presence of underlying structural heart disease, these conditions often lead to overt congestive failure.
Prognosis
Although several recent reports have suggested that the mortality for HF patients is improving, the overall mortality rate remains higher than for many cancers, including those involving the bladder, breast, uterus, and prostate. In the Framingham Study, the median survival was 1.7 years for men and 3.2 years for women, with only 25% of men and 38% of women surviving 5 years. European studies have confirmed a similar poor long-term prognosis ( Fig. 50.1 ). More recent data from the Framingham Study have examined long-term trends in the survival of patients with HF and shown improved survival in both men and women, with an overall decline in mortality of approximately 12% per decade from 1950 to 1999. Moreover, recent reports from Scotland, Sweden, and the United Kingdom also suggested that survival rates may be improving following hospital discharge. Of note, the mortality of HF in epidemiologic studies is substantially higher than that reported in clinical HF trials involving drug and/or device therapies, in which the mortality figures are often deceptively low because the patients enrolled in trials are younger, are more stable clinically, and tend to be followed more closely clinically.
The role of gender and HF prognosis remains a controversial issue with respect to HF outcomes. Nonetheless, the aggregate data suggest that women with HF have a better overall prognosis than do men. However, women appear to have a greater degree of functional incapacity for the same degree of LV dysfunction and also have higher prevalence of HF with a normal EF (see Chapter 51 ). Controversy has also arisen regarding the impact of race on outcome, with higher mortality rates being reported in blacks in some but not all studies. In the United States HF affects approximately 3% of blacks, whereas in the general population, the prevalence is about 2%. Blacks with HF present at an earlier age and have more advanced LV dysfunction and a worse New York Heart Association (NYHA) class at the time of diagnosis. Although the reasons for these differences are not known, as noted above, differences in HF etiology might explain some of these observations. There may also be additional socioeconomic factors that may influence outcomes in black patients, such as geographic location and access to health care. Age is one of the stronger and most consistent predictors of adverse outcome in HF (see Special Populations below).
Many other factors have been associated with increased mortality in HF patients ( Table 50.2 ). Most of the factors listed as outcome predictors have survived, at least, univariate analysis, with many standing out independently when multifactorial analysis techniques are employed. Nonetheless, it is extraordinarily difficult to determine which prognostic variable is most important to predicting individual patient outcome in either clinical trials or, more importantly, during the day-to-day management of an individual patient. To this end several multivariate models for predicting the HF prognosis have been developed and validated. The Seattle Heart Failure Model was derived by retrospectively investigating predictors of survival among HF patients in clinical trials. The Seattle Heart Failure Model provides an accurate estimate of 1-, 2-, and 3-year survival with the use of easily obtained clinical, pharmacologic, device, and laboratory characteristics, and is accessible free of charge to all health care providers as an interactive web-based program ( http://depts.washington.edu/shfm ).
TABLE 50.2
Etiology of Chronic Heart Failure
Myocardial Disease
Disorders of Rate and Rhythm
Pulmonary Heart Disease
Metabolic Disorders
Excessive Blood Flow Requirements
|
∗ Indicates conditions that can also lead to heart failure with a preserved ejection fraction.
Biomarkers and Prognosis (see also Chapter 48 )
The observation that the renin angiotensin-aldosterone, adrenergic, and inflammatory systems are activated in HF (see Chapter 47 ) has prompted the examination of the relationships between a variety of biochemical measurements and clinical outcomes ( Table 50.3 ). Strong inverse correlations have been reported between survival and plasma levels of norepinephrine, renin, arginine vasopressin (AVP), aldosterone, atrial and brain natriuretic peptides (BNP and NT-proBNP), endothelin-1, and inflammatory markers such as tumor necrosis factor (TNF), soluble TNF receptors, C reactive protein, galactin-3, pentraxin-3, and soluble ST2. The GUIDE-IT trial (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) was designed to prospectively study the relationship between change in natriuretic peptide concentration, cardiac remodeling, and clinical events in HFrEF patients. Although GUIDE-IT was stopped prematurely because biomarker-guided treatment was not more effective than usual care in improving outcomes, the Echocardiographic Substudy showed that lowering NT-proBNP to less than 1000 pg/mL by 12 months was associated with reverse LV remodeling and improved outcomes, regardless of the treatment strategy employed. These findings suggest the response to treatment as assessed by change in NT-proBNP is more important than the treatment strategy. Markers of oxidative stress, such as oxidized low-density lipoprotein and serum uric acid, have also been associated with worsening clinical status and impaired survival in patients with chronic HF. Cardiac troponin T and I, sensitive markers of myocyte damage, may be elevated in patients with nonischemic HF and predict adverse cardiac outcomes, as well as the development of incident HF. The association between a low hemoglobin/hematocrit and adverse HF outcomes has also long been recognized, and has garnered considerable recent attention after several reports illustrated the independent prognostic value of anemia in patients with HF with either reduced or normal ejection fraction.
Published estimates of the prevalence of anemia (defined as a hemoglobin concentration of <13 g/dL in men and <12 g/dL in women) in HF patients vary widely, ranging from 4% to 50% depending on the population studied and definition of anemia that is used. In general, anemia is associated with more HF symptoms, worse NYHA functional status, greater risk of HF hospitalization, and reduced survival. However, it is unclear whether anemia is a cause of decreased survival, or simply a marker of more advanced disease. The underlying cause for anemia is likely multifactorial, including reduced sensitivity to erythropoietin receptors, the presence of a hematopoiesis inhibitor, and/or a defective iron supply for erythropoiesis given as possible explanations.
A standard diagnostic workup should be undertaken in anemic HF patients, recognizing that no definite etiology is identified in many of these patients. Correctable causes of anemia should be treated according to practice guidelines. The role for blood transfusions in patients with cardiovascular disease is controversial. Although a “transfusion threshold” for maintaining the hematocrit greater than 30% in patients with cardiovascular disease has been generally been accepted, this clinical practice has been based more on expert opinion rather than on direct evidence that documents the efficacy of this form of therapy. Given the risks and costs of red blood cell transfusion, the evanescent benefits of blood transfusions in patients with chronic anemia, coupled with the unclear benefit in HF patients, the routine use of blood transfusion cannot be recommended for treating the anemia that occurs in stable HF patients. Treatment of anemic HF patients with mild to moderate anemia (hemoglobin level 9.0 to 12.0 g/dL) with the erythropoietin analog darbepoetin alpha was evaluated in the RED-HF (Reduction of Events With Darbepoetin Alfa in Heart Failure) trial. As shown in eFigure 50.1 there was no significant difference in the primary outcome variable of death from any cause or hospitalization for worsening HF (hazard ratio [HR] in the darbepoetin alfa group, 1.01; 95% confidence interval [CI] 0.90−1.13; P = 0.87), nor the secondary outcome (see eFig. 50.1B ) of cardiovascular death or time to first hospitalization for worsening HF (HR in the darbepoetin alfa group 10.01, 95% CI 0.89 to 1.14; P = 0.2). The lack of effect of darbepoetin alfa was consistent across all prespecified subgroups. Importantly, treatment with darbepoetin alfa led to an early (within 1 month) and sustained increase in the hemoglobin level throughout the study.
Iron deficiency is a common comorbidity in patients with HFrEF, and has been associated with increased mortality and a poorer quality of life, regardless of whether there is concomitant anemia. The definition of iron deficiency in HF differs from other conditions of chronic inflammation and is defined as: ferritin less than 100 μg/L or ferritin of 100 to 299 μg/L with a transferrin saturation less than 20%. Correction of iron deficiency in anemic and nonanemic patients with HFrEF (EF <30% to 45%) has been studied in several clinical trials. Two of the three randomized trials conducted thus far have used intravenous ferric carboxymaltose (FCM). Studies with FCM have demonstrated an improvement in symptoms, exercise capacity, and health-related quality of life; however, the effects on major clinical events remain uncertain. The one randomized clinical trial that used an oral iron polysaccharide (Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure [IRONOUT]; NCT02188784), did not show an improvement in peak V o 2 by cardiopulmonary exercise testing at 16 weeks. Based on the results of the randomized trials with intravenous iron supplementation, the current ACC/AHA/HFSA guidelines recommend (class IIb, LOE B-R) that intravenous iron replacement might be reasonable in patients with NYHA class II and III HF and iron deficiency (ferritin <100 ng/mL or 100 to 300 ng/mL if transferrin saturation is <20%) to improve functional status and quality of life. Although the US guidelines do not recommend any specific formulation, the European guidelines recommend treatment with IV FCM in symptomatic HF patients with iron deficiency to improve HF symptoms and quality of life (class IIa, Level of Evidence A recommendation).
TABLE 50.3
Prognostic Variable in Heart Failure Patients
Modified from Young JB. The prognosis of heart failure. In: Mann DL, eds. Heart Failure: A Companion to Braunwald’s Heart Disease . Philadelphia: Elsevier; 2004:489–506.
Demographics
Heart Failure Etiology
Comorbidities
Clinical Assessment
Hemodynamics
|
Exercise Testing
Metabolic
Chest X-ray
ECG
Biomarkers
Endomyocardial Biopsy
|
BNP , brain natriuretic peptides; BP , blood pressure; CAD , coronary artery disease; CI , cardiac index; COPD , chronic obstructive pulmonary disease; CRP , C-reactive protein; ESR , erythrocyte sedimentation rate; HR , hazard ratio; IDCM , idiopathic dilated cardiomyopathy; IL , interleukin; LVEF , left ventricular ejection fraction; NE , norepinephrine; NYHA , New York Heart Association; PAP , pulmonary artery pressure; PAP-PCWP , gradient across lung; PCWP , pulmonary capillary wedge pressure; PRA , plasma renin activity; RVEF , right ventricular ejection fraction; sST2 , soluble suppression of tumorigenesis-2; TNF , tumor necrosis factor; V co 2 , volume of exhaled carbon dioxide; VE , ventilation.
Renal Insufficiency (see also Chapter 101 )
Renal insufficiency is associated with poorer outcomes in patients with HF; however, there remains some uncertainty whether renal impairment is a simply a marker for worsening HF or whether renal impairment might be causally linked to worsening HF. Though more common in patients hospitalized for HF, at least some degree of renal impairment is still present in about half of stable HF outpatients. Patients with renal hypoperfusion or intrinsic renal disease show an impaired response to diuretics and angiotensin-converting enzymes inhibitors (ACEIs) and are at increased risk of adverse effects during treatment with digitalis. In a recent meta-analysis the majority of HF patients had some degree of renal impairment. These patients represented a high-risk group with an approximately 50% increased relative mortality risk when compared with patients who had normal renal function. Similar findings were observed in the Acute Decompensated Heart Failure National Registry (ADHERE) (see Chapter 49 ). In the Second Prospective Randomized Study of Ibopamine on Mortality and Efficacy, impaired renal function was a stronger predictor of mortality than impaired LV function and NYHA class in patients with advanced HF ( Fig. 50.2 ). Thus, renal insufficiency is a strong, independent predictor of adverse outcomes in HF patients. As will be discussed, below, treatment with sodium-glucose transporter-2 (SGLT2) inhibitors stabilizes renal function in patients with HFrEF.
Approach to the Patient
HFrEF should be viewed as continuum that is comprised of four interrelated stages (see Fig. 50.3 ). Stage A includes patients who are at high risk for developing HF, but without structural heart disease or symptoms of HF (e.g., patients with diabetes or hypertension). Stage B includes patients who have structural heart disease but without symptoms of HF (e.g., patients with a previous myocardial infarction [MI] and asymptomatic LV dysfunction). Stage C includes patients who have structural heart disease who have developed symptoms of HF (e.g., patients with a previous MI with shortness of breath and fatigue). Stage D includes patients who refractory HF requiring special interventions (e.g., patients with refractory HF who are awaiting cardiac transplantation). The clinical assessment of patients with HFrEF is discussed in detail in Chapter 48 , and the diagnosis and management of patients with HFpEF is discussed in detail in Chapter 51 .
Patients at High Risk for Developing Heart Failure (Stage A)
For patients at high risk of developing HFrEF, every effort should be made to prevent HF, using standard practice guidelines to treat preventable conditions that are known to lead to HF, including hypertension (see Chapter 26 ), hyperlipidemia (see Chapter 27 ), and diabetes (see Chapter 31 ). In this regard, ACEIs are particularly useful in preventing HF in patients who have a history of atherosclerotic vascular disease, diabetes mellitus, or hypertension with associated cardiovascular risk factors.
Population Screening
At present there is limited information available to support the screening of broad populations to detect undiagnosed HF and/or asymptomatic LV dysfunction. Although initial studies suggested that determination of BNP or NT-proBNP levels (see also Chapter 48 ) might be useful for screening, the positive predictive value for these tests in a low-prevalence and asymptomatic population for the purpose of detecting cardiac dysfunction varies among studies, and the possibility of false-positive results has significant cost-effectiveness implications.
Patients who are at very high risk of developing cardiomyopathy (e.g., those with a strong family history of cardiomyopathy or those receiving cardiotoxic interventions [see Chapter 56, Chapter 57 ]) are appropriate targets for more aggressive screening such as 2-D echocardiography to assess LV function. St Vincent’s Screening To Prevent Heart Failure (STOP-HF) showed that, in patients with known cardiovascular risk factors, screening with BNP testing followed by collaborative care between internists and cardiovascular specialists resulted in a significant reduction in LV dysfunction (odds ratio [OR], 0.55; 95% CI, 0.37 to 0.82; P = 0.003). Although there was no significant reduction in clinical HF events, there was a significant decrease in the incidence rates of emergency hospitalization for major cardiovascular events. However, the routine periodic assessment of LV function in low-risk patients is not currently recommended. Several sophisticated clinical scoring systems have been developed to screen for HF in population-based studies, including the Framingham Criteria, which screens for HF on the basis of clinical criteria, and the National Health and Nutrition Survey (NHANES) which uses self-reporting of symptoms to identify HF patients ( Table 50.4 ). However, as discussed in Chapter 48 , additional laboratory testing is usually necessary to definitively make the diagnosis of HF when these methodologies are used.
TABLE 50.4
Diagnostic Criteria for Heart Failure in Population-Based Studies
Modified from Ho KK, Pinsky JL, Kannel WB, et al. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol . 1993;22:6A–13A; and Schocken DD, Arrieta MI, Leaverton PE, et al. Prevalence and mortality rate of congestive heart failure in the United States. J Am Coll Cardiol . 1992;20:301–306.
| Framingham Criteria | ||
|---|---|---|
| Major Criteria | Minor Criteria | Major or Minor Criteria |
| Paroxysmal nocturnal dyspnea or orthopnea Neck-vein distention RALES Cardiomegaly Acute pulmonary edema S3 gallop Increased venous pressure >16 cm H 2 O Hepatojugular reflux |
Ankle edema Night cough Dyspnea on exertion Hepatomegaly Pleural effusion Vital capacity decreased one third from maximal capacity Tachycardia (rate >120/min) |
Weight loss >4.5 kg in 5 days in response to treatment |
| Nhanes Criteria | ||
|---|---|---|
| Categories | Criteria | Score |
| History | Dyspnea : Do you stop for breath when walking at an ordinary pace? |
1 |
| Do you stop for breath after walking for about 100 yards on flat ground? | 1 | |
| When hurrying on a hill | 2 | |
| When walking at an ordinary pace | 2 | |
| Physical examination | Heart rate: | |
| >110 beats/min | 1 | |
| 91–110 beats/min | 2 | |
| Jugular venous pressure (>6 cm H 2 O): | ||
| Alone | 1 | |
| Plus hepatomegaly or edema | 2 | |
| Rales : | ||
| Basilar crackles | 1 | |
| Crackles more than basilar crackles | 2 | |
| Chest radiography | Upper zone flow redistribution | 1 |
| Interstitial pulmonary edema | 2 | |
| Interstitial edema plus pleural fluid | 3 | |
| Alveolar fluid plus pleural fluid | 3 | |
The diagnosis of HF using the Framingham criteria requires the simultaneous presence of at least two major criteria or one major criterion in conjunction with two minor criteria. Minor criteria are acceptable only if they cannot be attributed to another medical condition (such as pulmonary hypertension, chronic lung disease, cirrhosis, ascites, or the nephrotic syndrome). NHANES-1 criteria: diagnosis of HF is score ≥three points.
NHANES , National Health and Nutrition Survey.
Management of Patients With Symptomatic and Asymptomatic Heart Failure
Transient Left Ventricular Dysfunction
As noted in Chapter 47 , the clinical syndrome of HF with reduced EF begins after an initial index event produces a decline in ejection performance of the heart. However, it is important to recognize that LV dysfunction may develop transiently in a variety of different clinical settings that may not invariably lead to the development of the clinical syndrome of HF. Figure 50.4 illustrates the important relationship between LV dysfunction (transient and sustained) and the clinical syndrome of HF (asymptomatic and symptomatic). LV dysfunction with pulmonary edema may develop acutely in patients with previously normal LV structure and function. This occurs most commonly postoperatively following cardiac surgery, or in the setting of severe brain injury, after a systemic infection, or after cessation of tachycardia. The general pathophysiologic mechanism involved is either some form of “stunning” of functional myocardium (see also Chapter 49 ), or activation of proinflammatory cytokines that are capable of suppressing LV function (see Chapter 47 ). Emotional stress can also precipitate severe, reversible LV dysfunction that is accompanied by chest pain, pulmonary edema, and cardiogenic shock in patients without coronary disease (Takotsubo syndrome [stress cardiomyopathy]). In this setting LV dysfunction is thought to occur secondary to the deleterious effects of catecholamines following heightened sympathetic stimulation. Microvascular dysfunction has been suggested as an important pathogenetic determinant of myocardial ischemia in Takotsubo syndrome. If LV dysfunction persists following the initial cardiac injury, patients may remain asymptomatic for a period of months to years; however, the weight of epidemiologic and clinical evidence suggests that at some point these patients will undergo the transition to overt symptomatic HF.
Defining the Appropriate Strategy (see Fig. 50.4 )
The main goals of treatment are to reduce symptoms, prolong survival, improve quality of life, and prevent disease progression. As will be discussed below, the current pharmacologic device, and surgical therapeutic armamentarium for the management of patients with a reduced EF allows health care providers to achieve each of these goals in the great majority of patients. Once patients have developed structural heart disease (Stage B to D), the choice of therapy for patients with HF with a reduced EF depends on their NYHA functional classification (see Chapter 48 , Table 48.1). Although this classification system is notoriously subjective, and has large interobserver variability, it has withstood the test of time and continues to be widely applied to patients with HF. For patients who have developed LV systolic dysfunction, but who remain asymptomatic (class I), the goal should be to slow disease progression by blocking neurohormonal systems that lead to cardiac remodeling (see Chapter 47 ). For patients who have developed symptoms (class II to IV), the primary goal should be to alleviate fluid retention, lessen disability, and reduce the risk of further disease progression and death. As will be discussed subsequently, these goals generally require a strategy that combines diuretics (to control salt and water retention) with neurohormonal interventions (to minimize cardiac remodeling).
General Measures
Identification and correction of the condition(s) responsible for the cardiac structural and/or functional abnormalities is critical (see Table 50.2 ), insofar as some of conditions that provoke LV structural and functional abnormalities are potentially treatable and/or reversible. Patients with HF often have multiple comorbid conditions that may interact with the syndrome of HF and or the choice of therapeutics. The 2013 ACC/AHA practice guidelines recognized the importance of comorbidities in HF, including hypertension, anemia, diabetes, arthritis, chronic kidney disease, and depression, but did not provide specific recommendations. However, the 2017 ACC/AHA/HFSA focused guideline update did provide specific recommendations for the treatment of hypertension, anemia, and sleep-disordered breathing. In addition to searching for reversible etiologies and comorbidities that contribute to the development of HF, it is equally important to identify factors that provoke worsening HF in stable patients ( Table 50.5 ). Among the most common causes of acute decompensation in a previously stable patient are dietary indiscretion and inappropriate reduction of HF therapy, either from patient self-discontinuation of medication, or alternatively from physician withdrawal of effective pharmacotherapy (e.g., because of concern over azotemia). HF patients should be advised to stop smoking and to limit alcohol consumption to two standard drinks per day in men or one standard drink per day in women. Patients suspected of having an alcohol-induced cardiomyopathy should be advised to abstain from alcohol consumption indefinitely. Excessive temperature extremes and heavy physical exertion should be avoided. Certain drugs are known to make HF worse and should also be avoided. For example, nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase-2 inhibitors (COX2), are not recommended in patients with chronic HF because the risk of renal failure and fluid retention is markedly increased in the setting of reduced renal function and/or ACEI use. Patients should be advised to weigh themselves on a regular basis to monitor weight gain and alert a health care provider or adjust their diuretic dose in the case of a sudden unexpected weight gain of greater than 3 to 4 pounds over a 3-day period. Although there is no documented evidence of the effects of immunization in HF patients, they are at high risk of developing pneumococcal disease and influenza. Accordingly, clinicians should consider recommending influenza and pneumococcal vaccines to their HF patient to prevent respiratory infections. It is equally important to educate the patient and family about HF, the importance of proper diet, as well the importance of compliance with the medical regimen. Supervision of outpatient care by a specially trained nurse or physician assistant and/or specialized HF clinics have all been found to be helpful, particularly in patients with advanced disease (see Disease Management below).
TABLE 50.5
Factors That May Precipitate Acute Decompensation in Patients with Chronic Heart Failure
From Mann DL. Heart Failure and Cor Pulmonale. In: Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine . 17th ed. New York: McGraw-Hill; 2007:1448.
|
HF , Heart failure; TNF , tumor necrosis factor.
Activity
Although heavy physical labor is not recommended for patients with HF, routine modest exercise has been shown to be beneficial in selected patients with NYHA class I to III HFrEF. The HF-ACTION trial (Controlled Trial Investigating Outcomes of Exercise Training) was a large multicenter randomized controlled study whose primary endpoint was a composite of all-cause mortality and all-cause hospitalization. Secondary endpoints included all-cause mortality, all-cause hospitalization, and the composite of cardiovascular mortality or HF hospitalization. HF-ACTION failed to show a significant improvement in all-cause mortality or all-cause hospitalization (HR, 0.93; 95% CI 0.84 to 1.02; p = 0.13) in patients who received a 12-week (3 times/wk) exercise training program followed by 25 to 30 minute, 5 days/wk home-based, self-monitored exercise workouts on a treadmill or stationary bicycle ( eFig. 50.2A ). Moreover, there was no difference in all-cause mortality (HR, 0.96; 95% CI 0.79 to 1.17; p = 0.70; eFig. 50.2B ). However, there was a trend towards decreased cardiovascular mortality or HF hospitalizations (HR, 0.87; 95% CI 0.74 to 0.99 p = 0.06) and quality of life was significantly improved in the exercise group. For euvolemic patients regular isotonic exercise such as walking or riding a stationary-bicycle ergometer may be useful as an adjunct therapy, to improve clinical status after patients have undergone exercise testing to determine suitability for exercise training (ensuring that patient does not develop significant ischemia or arrhythmias). Exercise training is not recommended, however, in HFrEF patients who have had a major cardiovascular event or procedure within the last 6 weeks, in patients receiving cardiac devices that limit the ability to achieve target heart rates, and in patients with significant arrhythmia or ischemia during baseline cardiopulmonary exercise testing.
Diet
Dietary restriction of sodium (2 to 3 g daily) is recommended in all patients with the clinical syndrome of HF and preserved or depressed EF. Further restriction (<2 g daily) may be considered in moderate to severe HF. Fluid restriction is generally unnecessary unless the patient is hyponatremic (<130 mEq/L), which may develop because of activation of the renin angiotensin system, excessive secretion of AVP, or loss of salt in excess of water from prior diuretic use. Fluid restriction (<2 L/day) should be considered in hyponatremic patients (<130 mEq/L), or for those patients whose fluid retention is difficult to control despite high doses of diuretics and sodium restriction. Caloric supplementation is recommended for patients with advanced HF and unintentional weight loss or muscle wasting (cardiac cachexia); however, anabolic steroids are not recommended for these patients because of the potential problems with volume retention. The measurement of nitrogen balance, caloric intake, and prealbumin may be useful in determining appropriate nutritional supplementation. The use of dietary supplements (“nutraceuticals”) should be avoided in the management of symptomatic HF because of the lack of proven benefit and the potential for significant interactions with proven HF therapeutics.
Management of Fluid Retention
Many of the clinical manifestations of the syndrome of HF result from excessive salt and water retention that leads to an inappropriate volume expansion of the vascular and extravascular space. The use of implantable devices to monitor HF is discussed in Chapter 58 . This chapter will focus on the use of diuretics in chronic HFrEF. Although both digitalis and low doses of ACEIs enhance urinary sodium excretion, few volume-overloaded HF patients can maintain proper sodium balance without the use of diuretic drugs. Indeed, attempts to substitute ACEIs for diuretics have been shown to lead to pulmonary edema and peripheral congestion. As shown in Figure 50.5 , diuretic-induced negative sodium and water balance can decrease LV dilation, functional mitral insufficiency, and decrease mitral wall stress and subendocardial ischemia. In short-term clinical trials diuretic therapy has led to a reduction in jugular venous pressures, pulmonary congestion, peripheral edema, and body weight, all of which were observed within days of initiation of therapy. In intermediate-term studies, diuretics have been shown to improve cardiac function, symptoms, and exercise tolerance in HF patients. To date, there have been no long-term studies of diuretic therapy in HF; thus, their effects on morbidity and mortality are not clearly known. Although retrospective analyses of clinical trials suggest that diuretic use is associated with worse clinical outcomes, a meta-analysis (Cochrane Review) suggested that treatment with diuretic therapy produced a significant reduction in mortality (OR 0.24; 95% CI 0.07 to 0.83; p = 0.02) and worsening HF (OR 0.07; 95% CI 0.01 to 0.52; p = 0.01). However, given the retrospective nature of this review, this analysis cannot be used as formal evidence to recommend the use diuretics to reduce HF mortality.
Diuretic Classes
A number of classification schemes have been proposed for diuretics on the basis of their mechanism of action, their anatomical locus of action within the nephron, and the form of diuresis that they elicit (solute versus water diuresis). The most common classification for diuretics employs an admixture of chemical (e.g., thiazide diuretic), site of action (e.g., loop diuretics), or clinical outcomes (e.g., potassium-sparing diuretics). The loop diuretics increase sodium excretion by up to 20% to 25% of the filtered load of sodium, enhance free water clearance, and maintain their efficacy unless renal function is severely impaired. In contrast, the thiazide diuretics increase the fractional excretion of sodium to only 5% to 10% of the filtered load, tend to decrease free water clearance, and lose their effectiveness in patients with impaired renal function (creatinine clearance <40 mL/min). Consequently, the loop diuretics have emerged as the preferred diuretic agents for use in most patients with HF. Diuretics that induce a water diuresis (aquaretics) include demeclocycline, lithium, and vasopressin V2 receptor antagonists, each of which inhibits the action of AVP on the collecting duct through different mechanisms, thereby increasing free water clearance. Drugs that cause solute diuresis are subdivided into two types: osmotic diuretics, which are nonresorbable solutes that osmotically retain water and other solutes in the tubular lumen; and drugs that selectively inhibit ion transport pathways across tubular epithelia, which constitute the majority of potent, clinically useful diuretics. The classes of diuretics and individual class members are listed in Table 50.6 and their renal sites of action are depicted in Figure 50.6 .
TABLE 50.6
Diuretics for Treating Fluid Retention in Chronic Heart Failure
Modified from Hunt SA, 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. J Am Coll Cardiol . 2005;46:e1–e82.
| DRUG | INITIAL DAILY DOSE(S) | MAXIMUM TOTAL DAILY DOSE | DURATION OF ACTION |
|---|---|---|---|
| Loop Diuretics ∗ | |||
| Bumetanide | 0.5–1.0 mg once or twice | 10 mg | 4–6 hr |
| Furosemide | 20–40 mg once or twice | 600 mg | 6–8 hr |
| Torsemide | 10–20 mg once | 200 mg | 12–16 hr |
| Ethacrynic acid | 25–50 mg once or twice | 200 mg | 6 hr |
| Thiazide Diuretics ∗∗ | |||
| Chlorothiazide | 250–500 mg once or twice | 1000 mg | 6–12 hr |
| Chlorthalidone | 25 mg once | 100 mg | 24–72 hr |
| Hydrochlorothiazide | 25 mg once or twice | 200 mg | 6–12 hr |
| Indapamide | 2.5 mg once | 5 mg | 36 hr |
| Metolazone | 2.5–5.0 mg once | 5 mg | 12–24 hr |
| Potassium-Sparing Diuretics | |||
| Amiloride | 5.0 mg once | 20 mg | 24 hr |
| Triamterene | 50–100 mg twice | 300 mg | 7–9 hr |
| AVP Antagonists | |||
| Satavaptan | 25 mg once | 50 mg once | NS |
| Tolvaptan | 15 mg once | 60 mg once | NS |
| Lixivaptan | 25 mg once | 250 mg twice | NS |
| Conivaptan (IV) | 20 mg IV loading dose followed by 20 mg continuous IV infusion/day |
100 mg once 40 mg IV |
7–9 hr |
| Sequential Nephron Blockade | |||
| Metolazone | 2.5–10 mg once plus loop diuretic | ||
| Hydrochlorothiazide | 25–100 mg once or twice plus loop diuretic | ||
| Chlorothiazide (IV) | 500–1000 mg once plus loop diuretic | ||
Unless indicated, all doses are for oral diuretics.
mg , Milligrams; IV , intravenous. NS , not specified.
∗ Equivalent doses: 40 mg furosemide = 1 mg bumetanide = 20 mg torsemide = 50 mg of ethacrynic acid.
∗∗ Do not use if estimated glomerular filtration is less than 30 mL/min or with cytochrome 3A4 inhibitors.
Loop Diuretics
The agents classified as loop diuretics, including furosemide, bumetanide, and torsemide, act by competing with chloride for binding to the Na + -K + -2Cl − symporter (NKCC2) on the apical membrane of epithelial cells in the thick ascending loop of Henle (site II, Fig. 50.6 ). Because furosemide, bumetanide, and torsemide are bound to plasma proteins, delivery of these drugs to the tubule by filtration is limited. However, these drugs are secreted efficiently into the tubular lumen by organic anion transporters (OAT1 and OAT2) at the basolateral membrane of proximal convoluted tubule epithelial cells and by multidrug resistance–associated protein 4 (and others) at the apical membrane or these cells. Thus, the efficacy of loop diuretics is dependent upon sufficient renal plasma blood flow and proximal tubular secretion to deliver these agents to their site of action. Probenecid shifts the plasma concentration-response curve for furosemide to the right by competitively inhibiting furosemide excretion by the organic acid transport system. The bioavailability of furosemide ranges from 40% to 70% of the oral dose. In contrast the oral bioavailability of bumetanide and torsemide exceed 80%. Accordingly, these agents may be more effective in advanced HF or those with right-sided HF, albeit at considerably greater cost. Agents in a second functional class of loop diuretics typified by ethacrynic acid exhibit a slower onset of action and have delayed and only partial reversibility. Ethacrynic acid may be safely used in sulfa-allergic HF patients.
Mechanisms of Action
Loop diuretics are believed to improve symptoms of congestion by several mechanisms. First, loop diuretics reversibly bind to and reversibly inhibit the action of the Na + -K + -2Cl − cotransporter, thereby preventing salt transport in the thick ascending loop of Henle. Inhibition of this symporter also inhibits Ca ++ and Mg ++ resorption by abolishing the transepithelial potential difference that is the driving force for absorption of these cations. By inhibiting the concentration of solute within the medullary interstitium, these drugs also reduce the driving force for water resorption in the collecting duct, even in the presence of AVP (see also Chapter 47 ). The decreased resorption of water by the collecting duct results in the production of urine that is nearly isotonic with plasma. The increase in delivery of Na + and water to the distal nephron segments also markedly enhances K + excretion, particularly in the presence of elevated aldosterone levels.
Loop diuretics also exhibit several characteristic effects on intracardiac pressure and systemic hemodynamics. Furosemide acts as a venodilator and reduces right atrial and pulmonary capillary wedge pressure within minutes when given intravenously (0.5 to 1.0 mg/kg). Similar data, although not as extensive, have accumulated for bumetanide and torsemide. This initial improvement in hemodynamics may be secondary to the release of vasodilatory prostaglandins, insofar as studies in animals and humans have demonstrated that the venodilatory actions of furosemide are inhibited by indomethacin. There have also been reports of an acute rise in systemic vascular resistance with in response to loop diuretics, which has been attributed to transient activation of the systemic or intravascular renin-angiotensin system (RAS), which is secondary to loop diuretics directly stimulating renin secretion by macula densa cells.
The potentially deleterious rise in LV afterload reinforces the importance of initiating vasodilator therapy with diuretics in patients with acute pulmonary edema and adequate blood pressure (see Chapter 49 ).
Thiazide and Thiazide-Like Diuretics
The benzothiadiazides, also known as thiazide diuretics , were the initial class of drugs that were synthesized to block the Na + -Cl − transporter in the cortical portion of the ascending loop of Henle and the distal convoluted tubule (site III, Fig. 50.6 ). Subsequently, drugs that share similar pharmacologic properties became known as thiazide-like diuretics, even though they were technically not benzothiadiazine derivatives. Metolazone, a quinazoline sulfonamide, is a thiazide-like diuretic that is used in combination with furosemide, in patients who become resistant to diuretics (see below). Because thiazide and thiazide-like diuretics prevent maximal dilution of urine, they decrease the kidney’s ability to increase free water clearance and may therefore contribute to the development of hyponatremia. Thiazides increase Ca 2+ resorption in the distal nephron ( Fig. 50.6 ) by several mechanisms, occasionally resulting in a small increase in serum Ca 2+ levels. In contrast, Mg 2+ resorption is diminished and hypomagnesemia may occur with prolonged use. Increased delivery of NaCl and fluid into the collecting duct directly enhances K + and H + secretion by this segment of the nephron, which may lead to clinically important hypokalemia.
Mechanisms of Action
The site of action of these drugs within the distal convoluted tubule has been identified as the Na + -Cl − symporter of the distal convoluted tubule. Although this cotransporter shares approximately 50% amino acid homology with the Na + /K + /2Cl − symporter of the ascending limb of the loop of Henle, it is insensitive to the effects of furosemide. This cotransporter (or related isoforms) is also present on cells within the vasculature and many cell types within other organs and tissues and may contribute to some of the other actions of these agents, such as their utility as antihypertensive agents. Similar to the loop diuretics, the efficacy of thiazide diuretics is dependent, at least in part, upon proximal tubular secretion to deliver these agents to their site of action. However, unlike the loop diuretics the plasma protein binding varies considerably among the thiazide diuretics; accordingly, this parameter will determine the contribution that glomerular filtration makes to tubular delivery of a specific diuretic.
Mineralocorticoid Receptor Antagonists
Mineralocorticoids (MRAs) such as aldosterone cause retention of salt and water and increase the excretion of K + and H + by binding to specific MRA receptors. Spironolactone (first-generation MRA) and eplerenone (second-generation MRA) are synthetic MRA receptors that act on the distal nephron to inhibit Na + /K + exchange at the site of aldosterone action (Site IV, Fig. 50.6 ).
Mechanisms of Action
Spironolactone has antiandrogenic and progesterone-like effects, which may cause gynecomastia or impotence in men, and menstrual irregularities in women. To overcome these side effects, eplerenone was developed by replacing the 17 alpha-thioacetyl group of spironolactone with a carbomethoxy group. As a result of this modification, eplerenone has greater selectivity for the MRA receptor than for steroid receptors and has less sex hormone side effects than does spironolactone. Eplerenone is further distinguished from spironolactone by its shorter half-life and the fact that it does not have any active metabolites. Although spironolactone and eplerenone are both weak diuretics, clinical trials have shown that both of these agents have profound effects on cardiovascular morbidity and mortality ( Fig. 50.7 ) by virtue of their ability to antagonize the deleterious effects of aldosterone in the cardiovascular system (see Chapter 47 ). Hence these agents are used in HF for their ability to antagonize the renin angiotensin aldosterone system (see below), rather than for their diuretic properties. Spironolactone (see Table 50.6 ) and its active metabolite, canrenone, competitively inhibit the binding of aldosterone to MRA or type I receptors in many tissues, including epithelial cells of the distal convoluted tubule and collecting duct. These cytosolic receptors are ligand-dependent transcription factors, which upon binding of the ligand (e.g., aldosterone), translocate to the nucleus where they bind to hormone response elements present in the promoter of some genes, including several involved in vascular and myocardial fibrosis, inflammation, and calcification.
While first- and second-generation steroid-based MRAs have been shown to reduce HF mortality rates, the broader use of these agents in HF patients has been limited by significant side effects, most notably hyperkalemia. Novel, potent, and selective “third-generation” nonsteroidal MRAs that combine the potency and efficacy of spironolactone with the selectivity of eplerenone, and have less hyperkalemia, have recently entered clinical trials. Finerenone (BAY 94-8862) is a nonsteroidal MRA that was compared to eplerenone in patients with worsening chronic HF and type 2 diabetes mellitus and/or chronic kidney disease in the phase IIb ARTS-HF (MinerAlocorticoid-Receptor antagonist Tolerability Stud) trial. ARTS-HF was a randomized, double-blind, comparator-controlled multicenter trial in 1066 patients with HF (left ventricular ejection fraction [LVEF] ≤40%). The primary endpoint was the percentage of individuals with a decrease of greater than 30% in plasma NT-proBNP from baseline to Day 90. When compared with eplerenone, finerenone was well tolerated and resulted in a 30% or greater decrease in NT-proBNP levels, which was similar to the proportion of patients observed in the eplerenone-treatment group. The composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90, which was a prespecified secondary endpoint occurred less frequently in all finerenone-dose groups except for the lowest doses.
Potassium-Sparing Diuretics
Triamterene and amiloride are referred to as potassium-sparing diuretics . These agents share the common property of causing a mild increase in NaCl excretion, as well as having antikaluretic properties. Triamterene is a pyrazinoylguanidine derivative, whereas amiloride is a pteridine. Both drugs are organic bases that are transported into the proximal tubule, where they block Na + reabsorption in the late distal tubule and collecting duct (site IV, Fig. 50.7 ). However, since Na + retention occurs in more proximal nephron sites in HF, neither amiloride nor triamterene is effective in achieving a net negative Na + balance when given alone in HF patients. Both amiloride and triamterene appear to share a similar mechanism of action. Considerable evidence suggests that amiloride blocks Na + channels in the luminal membrane of the principal cells in the late distal tubule and collecting duct, perhaps by competing with Na + for negatively charged areas within the pore of the Na + channel. Blockade of Na + channels leads to hyperpolarization of the luminal membrane of the tubule, which reduces the electrochemical gradient that provides the driving force for K + secretion into the lumen. Amiloride and its congeners also inhibit Na + /H + antiporters in renal epithelial cells and in many other cell types, but only at concentrations that are higher than those used clinically.
Carbonic Anhydrase Inhibitors
The zinc metalloenzyme carbonic anhydrase plays an essential role in the NaHCO 3 resorption and acid secretion in the proximal tubule (site I, see Fig. 50.6 ). Although weak diuretics, carbonic anhydrase inhibitors (see Table 50.6 ) such as acetazolamide, potently inhibit carbonic anhydrase, resulting in near-complete loss of NaHCO 3 resorption in the proximal tubule. The use of these agents in patients with HF is confined to temporary administration to correct the metabolic alkalosis that occurs as a “contraction” phenomenon in response to the administration of other diuretics. When used repeatedly, these agents can lead to metabolic acidosis as well as severe hypokalemia.
Sodium-Glucose Transporter-2 Inhibitors
The SGLT2 is a high-capacity, low-affinity transporter that is located in the S1 and S2 segments of the proximal tubule in the kidneys (Site I, Fig. 50.6 ). SGLT2 accounts for 90% of glucose reabsorption by the kidney, whereas the lower-capacity higher-affinity SGLT1, located in the S3 segment of the proximal tubules, accounts for the remaining 10% of glucose absorption. SGLT2 is also responsible for proximal tubular reabsorption of sodium, and the passive absorption of chloride that is driven by the resulting electrochemical gradient in the proximal tubule lumen. The increased absorption of sodium and chloride in the proximal tubule results in lower chloride concentration delivered to the macula densa, which in turn results in dilation of the afferent arteriole and increased glomerular filtration through “tubulo-glomerular feedback,” which preserves renal blood flow and glomerular filtration rate.
SGLT2 inhibitors result in a 1:1 stoichiometric inhibition of sodium and glucose uptake in the proximal tubule of the kidney. This leads to contraction of the plasma volume and modest lowering of blood pressure, without activation of the sympathetic nervous system. The contraction of plasma volume may contribute to changes in markers of hemoconcentration with SGLT2 inhibitors, including increases in blood urea nitrogen and hematocrit, although the latter may also be on the basis of increased erythropoiesis. In addition, the proximal natriuresis that occurs with SGLT2 inhibition results in afferent arteriole vasoconstriction through tubulo-glomerular feedback, thereby reducing glomerular hyperfiltration ( Fig. 50.8 ). Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. Beyond effects on traditional cardiovascular risk factors such as HbA 1c and weight, SGLT2 inhibition also reduces plasma uric acid levels by 10% to 15% by increasing uricosuria via exchange of filtered glucose. Elevated uric acid levels have been implicated in worsening HF because of oxidative stress and inflammation.
Vasopressin Antagonists
As discussed in Chapter 47 , increased circulating levels of the pituitary hormone AVP contribute to the increased systemic vascular resistance and positive water balance in HF patients. The cellular effects of AVP are mediated by interactions with three types of receptors, V 1a , V 1b , and V 2 (see Chapter 47 ). Selective V 1a antagonists block the vasoconstricting effects of AVP in peripheral vascular smooth muscle cells, whereas V 2 selective receptor antagonists inhibit recruitment of aquaporin water channels into the apical membranes of collecting duct epithelial cells, thereby reducing the ability of the collecting duct to resorb water. Combined V 1a /V 2 antagonists lead to a decrease in systemic vascular resistance and prevent the dilutional hyponatremia that occurs in HF patients.
The AVP antagonists or “vaptans” (see Table 50.6 ) were developed to selectively block the V 2 receptor (e.g., tolvaptan, lixivaptan, satavaptan) or nonselectively block both the V 1a /V 2 receptors (e.g., conivaptan). All four AVP antagonists increase urine volume, decrease urine osmolarity, and have no effect on 24-hour sodium excretion (see also Chapter 49 ) Long-term therapy with the V 2 selective vasopressin antagonist tolvaptan did not improve mortality but appears to be safe in patients with advanced HF. Currently two vasopressin antagonists are Food and Drug Administration (FDA)-approved (conivaptan and tolvaptan) for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum Na + ≤125) that is symptomatic and which resisted correction with fluid restriction in patients with HF; however, neither of these agents is currently specifically approved for the treatment of HF. Use of these agents is appropriate after traditional measures to treat hyponatremia have been tried, including water restriction and maximization of medical therapies such as ACEIs or angiotensin receptor blockers (ARBs) which block or decrease angiotensin II. The use of vaptans in hospitalized HF patients is discussed in Chapter 49 .
Diuretic Treatment of Heart Failure
Patients with evidence of volume overload or a history of fluid retention should be treated with a diuretic to relieve their symptoms. In symptomatic patients, diuretics should be always used in combination with neurohormonal antagonists that are known to prevent disease progression. When patients have moderate to severe symptoms or renal insufficiency, a loop diuretic is generally required. Diuretics should be initiated in low doses (see Table 50.6 ) and then titrated upward to relieve signs and symptoms of fluid overload. A typical starting dose of furosemide for patients with systolic HF and normal renal function is 40 mg, although doses of 80 to 160 mg are often necessary to achieve adequate diuresis. Loop diuretics have a sigmoidal dose-response curve. Importantly, in both HF and renal insufficiency, the dose response for loop diuretics shifts downward and to the right ( Fig. 50.9A ). Because of the steep dose-response curve and effective threshold for loop diuretics (see Fig. 50.9B ), it is critical to find an adequate dose of loop diuretic that leads to a clear-cut diuretic response. One commonly employed method for finding the appropriate dose is to double the dose until the desired effect is achieved, or the maximal dose of diuretic is reached. Once patients have achieved an adequate diuresis, it is important to document their “dry weight” and make certain that patients weigh themselves daily in order to maintain their dry weight.
Although furosemide is the most commonly used loop diuretic, the oral bioavailability of furosemide is approximately 40% to 79%. Therefore, bumetanide or torsemide may be preferable because of their increased bioavailability. With the exception of torsemide, the commonly used loop diuretics are short-acting (<3 hours). For this reason, loop diuretics usually need to be given at least twice daily. Some patients may develop hypotension or azotemia during diuretic therapy. While the rapidity of diuresis should be slowed in these patients, diuretic therapy should be maintained at a lower level until the patient becomes euvolemic, insofar as persistent volume overload may compromise the effectiveness of some neurohormonal antagonists. Intravenous administration of diuretics may be necessary to relieve congestion acutely (see Fig. 50.9B and Chapter 49 ), and can be done safely in the outpatient setting. After a diuretic effect is achieved with short-acting loop diuretics, increasing administration frequency to twice or even three times per day will provide more diuresis with less physiologic perturbation than larger single doses. Once the congestion has been relieved, treatment with diuretics is continued to prevent the recurrence of salt and water retention in order to maintain the patient’s ideal dry weight.
Complications of Diuretic Use
Patients with HF who are receiving diuretics should be monitored for complications of diuretics on a regular basis. The major complications of diuretic use include electrolyte and metabolic disturbances, volume depletion, as well as worsening azotemia. The interval for reassessment should be individualized based on severity of illness and underlying renal function, the use of concomitant medications such as ACEIs, ARBs and aldosterone antagonists, the past history of electrolyte imbalances, and/or need for more aggressive diuresis.
Electrolyte and Metabolic Disturbances
Diuretic use can lead to potassium depletion, which can predispose the patient to significant cardiac arrhythmias. Renal potassium losses from diuretic use can be also exacerbated by the increase in circulating levels of aldosterone observed in patients with advanced HF, as well by the marked increases in distal nephron Na + delivery that follow use of either loop or distal nephron diuretics. The level of dietary salt intake may also contribute to the extent of renal K + wasting with diuretics.
In the absence of formal guidelines with respect to the level of maintenance of serum K + levels in HF patients, many experienced HF clinicians have advocated that the serum K + should be maintained between 4.0 and 5.0 mEq/L because HF patients are often treated with pharmacologic agents that are likely to provoke proarrhythmic effects in the presence of hypokalemia (e.g., digoxin, type III antiarrhythmics, beta-agonists, or phosphodiesterase inhibitors). Hypokalemia can be prevented by increasing the oral intake of KCL. The normal daily dietary K + intake is approximately 40 to 80 mEq. Therefore, to increase this by 50% requires an additional 20 to 40 mEq K + supplementation daily. However, in the presence of alkalosis, hyperaldosteronism, or Mg 2+ depletion, hypokalemia is quite unresponsive to increased dietary intake of KCL, and more aggressive replacement is necessary. If supplementation is necessary, oral potassium supplements in the form of KCL extended-release tablets or liquid concentrate should be used whenever possible. Intravenous potassium is potentially hazardous and should be avoided except in emergencies. Where appropriate, the use of an MRA may also prevent the development of hypokalemia.
The use of aldosterone-receptor antagonists is often associated with the development of life-threatening hyperkalemia, particularly when they are combined with ACEIs, ARBs, or angiotensin receptor-neprilysin inhibitors (ARNIs). Potassium supplementation is generally stopped after the initiation of aldosterone antagonists, and patients should be counseled to avoid high potassium–containing foods. The management of acute hyperkalemia (>6.0 mEq/L) may require a short-term cessation of potassium-retaining agents and/or renin-angiotensin-aldosterone system (RAAS) inhibitors; however, RAAS inhibitors should be carefully reintroduced as soon as possible while monitoring potassium levels. Two new potassium binders, patiromer and sodium zirconium cyclosilicate, have been studied in HF patients with hyperkalemia. Patiromer is a nonabsorbed, cation-exchange polymer that contains a calcium-sorbitol counterion, and works by binding potassium in the lumen of the gastrointestinal tract, resulting in a reduction of serum-potassium levels within 7 hours of the first dose. Patiromer is FDA-approved for the treatment of hyperkalemia, but should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action. The initial clinical studies in patients with HF have shown that these therapies reduce serum potassium and prevent recurrent hyperkalemia in HF patients with chronic kidney disease who were receiving RAAS inhibitors.
Diuretics may be associated with multiple other metabolic and electrolyte disturbances, including hyponatremia, hypomagnesemia, metabolic alkalosis, hyperglycemia, hyperlipidemia, and hyperuricemia. Hyponatremia is usually observed in HF patients with very high degrees of RAAS activation and/or AVP levels. Aggressive diuretic use can also lead to hyponatremia. Hyponatremia can typically be treated by more stringent water restriction. Both loop and thiazide diuretics can cause hypomagnesemia, which can aggravate muscle weakness and cardiac arrhythmias. Magnesium replacement should be administered for signs or symptoms of hypomagnesemia (arrhythmias, muscle cramps), and can be routinely given (with uncertain benefit) to all subjects receiving large doses of diuretics or requiring large amounts of K + replacement. The modest hyperglycemia and/or hyperlipidemia produced by thiazide diuretics is not usually clinically important, and blood glucose and lipids are usually easily controlled using standard practice guidelines. Metabolic alkalosis can generally be treated by increasing KCL supplementation, lowering diuretic doses, or transiently using acetazolamide.
Hypotension and Azotemia
The excessive use of diuretics can lead to a decreased blood pressure, decreased exercise tolerance, and increased fatigue, as well as impaired renal function. Hypotensive symptoms usually resolve after a decrease in the dose or frequency of diuretics in patients who are volume depleted. However, in most instances the use of diuretics is associated with decrease in blood pressure and/or mild azotemia that do not lead to patient symptoms. In this instance reductions in the diuretic dose are not necessary, particularly if the patient remains edematous. In some patients with advanced, chronic HF, elevated BUN and creatinine concentrations may be necessary to maintain control of congestive symptoms.
Neurohormonal Activation
Diuretics may increase the activation of endogenous neurohormonal systems in HF patients, which can lead to disease progression unless patients are receiving treatment with a concomitant neurohormonal antagonist (e.g., ACEI or beta-blocker).
Ototoxicity
Ototoxicity, which is more frequent with ethacrynic acid than the other loop diuretics, can manifest as tinnitus, hearing impairment, and deafness. Hearing impairment and deafness are usually, but not invariably, reversible. Ototoxicity occurs most frequently with rapid intravenous injections, and least frequently with oral administration.
Diuretic Resistance and Management
One of the inherent limitations of diuretics is that they achieve water loss via excretion of solute at the expense of glomerular filtration, which in turn activates a set of homeostatic mechanisms that ultimately limit their effectiveness. In normal subjects the magnitude of natriuresis following a given dose of diuretic declines over time as a result of the so-called “braking phenomenon” (see Fig. 50.9C ). Studies have shown that the time-dependent decline in natriuresis for a given diuretic dose is critically dependent upon reduction of the extracellular fluid volume, which leads to an increase in solute and fluid reabsorption in the proximal tubule. In addition, contraction of the extracellular volume can lead to stimulation of efferent sympathetic nerves, which reduces urinary Na + excretion by reducing renal blood flow, stimulating renin (and ultimately aldosterone) release, which in turn stimulates Na + reabsorption along the nephron (see also Chapter 47 ). The magnitude of the natriuretic effect of potent loop diuretics may also decline in HF patients, particularly as HF progresses. Although the bioavailability of these diuretics is generally not decreased in HF, the potential delay in their rate of absorption may result in peak drug levels within the tubular lumen in the ascending loop of Henle that are insufficient to induce maximal natriuresis. The use of intravenous formulations may obviate this problem (see Chapter 49 ). However, even with intravenous dosing, a rightward shift of the dose-response curve is observed between the diuretic concentration in the tubular lumen and its natriuretic effect in HF (see Fig. 50.9A ). Moreover, the maximal effect (ceiling) is lower in HF. This rightward shift has been referred to as “diuretic resistance” and is likely due to several factors in addition to the braking phenomenon described above. First, most loop diuretics (with the exception of torsemide) are short-acting drugs. Accordingly, after a period of natriuresis, the diuretic concentration in plasma and tubular fluid declines below the diuretic threshold. In this situation, renal Na + reabsorption is no longer inhibited and a period of antinatriuresis or postdiuretic NaCl retention ensues. If dietary NaCl intake is moderate to excessive, postdiuretic NaCl retention may overcome the initial natriuresis in patients with excessive activation of the adrenergic nervous system and RAS. This observation forms the rationale for administering short-acting diuretics several times per day to obtain consistent daily salt and water loss. Second, there is a loss of renal responsiveness to endogenous natriuretic peptides as HF advances (see Chapter 47 ). Third, diuretics increase solute delivery to distal segments of the nephron, causing epithelial cells to undergo both hypertrophy and hyperplasia. Although the diuretic-induced signals that initiate changes in distal nephron structure and function are not well understood, chronic loop diuretic administration increases the Na-K-ATPase activity in the distal collecting duct and cortical collecting tubule, as well as increases the number of thiazide-sensitive Na-Cl cotransporters in the distal nephron, which increases the solute resorptive capacity of the kidney as much as threefold.
In patients with HF an abrupt decline in cardiac and/or renal function or patient noncompliance with their diuretic regimen or diet may lead to diuretic resistance. Apart from these more obvious causes, it is important to query the patient with regard to the concurrent use of drugs that adversely affect renal function, such as NSAIDs and COX-2 inhibitors (see Table 50.5 ), and certain antibiotics (trimethoprim and gentamicin). The relative risk of increased HF hospitalization varies between individual NSAIDs; including a 1.16 (95% CI 1.07 to 1.27) increase for naproxen, a 1.18 (95% CI 1.12 to 1.23) increase for ibuprofen, a 1.19 (1.15 to 1.24) increase for diclofenac, and a 1.51 (95% 1.33 to 1.71) increase for indomethacin. The use of the COX-2 inhibitors, etoricoxib and rofecoxib, was also associated with increased risk of hospitalization. The insulin-sensitizing thiazolidinediones (TZDs) have also been linked to increased fluid retention in patients with HF, although the clinical significance of this finding is not known. It has been suggested that TZDs activate proliferator-activated receptor-gamma expression in the renal collecting duct, which enhances expression of cell-surface epithelial Na + channels. Moreover, studies in healthy men have shown that pioglitazone stimulates plasma renin activity that may contribute to increased Na + retention. Rarely, drugs such as probenecid, or high plasma concentrations of some antibiotics, may compete with the organic ion transporters in the proximal tubule responsible for the transfer of most diuretics from the recirculation into the tubular lumen. The use of increasing doses of vasodilators, with or without a marked decline in intravascular volume as a result of concomitant diuretic therapy, may lower renal perfusion pressure below that necessary to maintain normal autoregulation and glomerular filtration in patients with RAS from atherosclerotic disease. Accordingly, a reduction in renal blood flow may occur despite an increase in cardiac output, thereby leading to a decrease in diuretic effectiveness.
A patient with HF may be considered to be resistant to diuretic drugs when moderate doses of a loop diuretic do not achieve the desired reduction of the extracellular fluid volume. In outpatients, a common and useful method for treating the diuretic-resistant patient is to administer two classes of diuretic concurrently. Adding a proximal tubule diuretic or a distal collecting tubule diuretic to a regimen of loop diuretics is often dramatically effective (“sequential nephron blockade”). As a general rule, when adding a second class of diuretic the dose of loop diuretic should not be altered, because the shape of the dose-response curve for loop diuretics is not affected by the addition of other diuretics, and the loop diuretic must be given at an effective dose for it to be effective. The combination of loop and distal collecting tubule diuretics has been shown to be effective through several mechanisms. One is that distal collecting tubule diuretics have longer half-lives than loop diuretics and may thus prevent or attenuate postdiuretic NaCl retention. A second mechanism by which distal collecting tubule diuretics potentiate the effects of loop diuretics is by inhibiting Na + transport along the proximal tubule, insofar as most thiazide diuretics also inhibit carbonic anhydrase. They also inhibit NaCl transport along the distal renal tubule, which may counteract the increased solute resorptive effects of the hypertrophied and hyperplastic distal epithelial cells.
The selection of a distal collecting tubule diuretic to use as second diuretic is a matter of choice. Many clinicians choose metolazone because its half-life is longer than that of some other distal collecting tubule diuretics, and because it has been reported to remain effective even when the glomerular filtration rate is low. However, direct comparisons between metolazone and several traditional thiazides have shown little difference in natriuretic potency when they are included in a regimen with loop diuretics in HF patients. Distal collecting tubule diuretics may be added in full doses (50 to 100 mg/day hydrochlorothiazide or 2.5 to 10 mg/day metolazone; see Table 50.6 ) when a rapid and robust response is needed. However, such an approach is likely to lead to excessive fluid and electrolyte depletion if patients are not followed up extremely closely. One reasonable approach to combination therapy is to achieve control of fluid overload by initially adding full doses of distal collecting tubule diuretic on a daily basis and then decreasing the dose of this diuretic to three times weekly to avoid excessive diuresis. An alternative strategy in hospitalized patients is to administer the same daily parenteral dose of a loop diuretic by continuous intravenous infusion, which leads to sustained natriuresis because of the continuous presence of high drug levels within the tubular lumen (see also Chapter 49 ), and avoids postdiuretic (“rebound”) resorption of Na + (see Fig. 50.9C ). This approach requires the use of a constant-infusion pump but permits more precise control of the natriuretic effect achieved over time, particularly in carefully monitored patients. It also diminishes the potential for a too-rapid decline in intravascular volume and hypotension as well as the risk of ototoxicity in patients given large bolus intravenous doses of a loop diuretic. A typical continuous furosemide is initiated with a 20- to 40-mg intravenous loading dose as a bolus injection, followed by a continuous infusion of 5 to 10 mg/hr for a patient who had been receiving 200 mg of oral furosemide per day in divided doses. The Diuretic Optimal Strategy Evaluation in Acute Heart Failure (DOSE) study showed that there was no significant difference in patient symptoms or renal function when patients with acute decompensated HF were treated by an IV bolus of furosemide compared to IV infusion of furosemide (see Chapter 49 ), suggesting that whichever approach is most likely to reliably produce the desired dieresis should be used.
Another common reason for diuretic resistance in advanced HF is the development of the cardiorenal syndrome (see also Chapter 101, Chapter 49 ), which is recognized clinically as worsening renal function that limits diuresis in patients with obvious clinical volume overload. In patients with advanced HF the cardiorenal syndrome is frequently present in patients who have repeated HF hospitalizations, and in whom adequate diuresis is difficult to obtain because of worsening indices of renal function. This impairment in renal function often is dismissed as “pre-renal”; however, when measured carefully, neither cardiac output nor renal perfusion pressure have been shown to be reduced in diuretic-treated patients who develop cardiorenal syndrome. Importantly, worsening indices of renal function contribute to longer hospital stays, and predict higher rates of early rehospitalization and death. The mechanisms for and treatment of the cardiorenal syndrome remain poorly understood.
Device-Based Therapies for Management of Fluid Status (See also Chapter 58 )
The use of mechanical methods of fluid removal, such as extracorporeal ultrafiltration (UF), may be needed to achieve adequate control of fluid retention, particularly in patients who become resistant and/or refractory to diuretic therapy. Extracorporeal UF removes salt and water isotonically by driving the patient’s blood through a highly permeable filter via an extracorporeal circuit in an arteriovenous or venovenous mode. Alternative extracorporeal methods include continuous hemofiltration, continuous hemodialysis, or continuous hemodiafiltration. With slow continuous UF, the patient’s intravascular fluid volume remains stable as fluid shifts from the extravascular space into the intravascular space, with the result that there is no deleterious activation of neurohormonal systems. UF has been shown to reduce right atrial and pulmonary artery wedge pressures and increase cardiac output, diuresis, and natriuresis without changes in heart rate, systolic blood pressure, renal function, electrolytes, or intravascular volume.
The Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure (RAPID-CHF) trial, which was the first randomized controlled trial of UF for acute decompensated HF, enrolled 40 patients who were randomized to receive either usual care (diuretic) or a single 8-hour UF (using a proprietary device) in addition to usual care. The primary endpoint was weight loss 24 hours after enrollment. Fluid removal after 24 hours was approximately twofold greater in the UF group. The Ultrafiltration versus IV Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) compared the long-term safety and efficacy of UF therapy (using a proprietary device) to intravenous diuretics in a multicenter trial involving 200 patients, who were assessed at entry and at intervals out to 90 days. The primary endpoint of the trial was total weight loss during the first 48 hours of randomization and the change in dyspnea score during the first 48 hours of randomization. Although the two treatments were similar in their ability to relieve dyspnea, UF was associated with significantly greater fluid loss over 48 hours and a lower rate of rehospitalization during the next 90 days. The use of UF in high-risk patients who are developing the cardiorenal syndrome was explored in the Cardiorenal Rescue Study in Acute Decompensated HF (CARRESS) trial, which showed that UF resulted in similar weight loss, but resulted in an increase in creatinine levels, compared to standard care, and was associated with more serious adverse events and intravenous catheter-related complications (see Chapter 49 ).
Given the cost, need for venous access, and the nursing support necessary to implement UF, this intervention will require additional studies to determine its role in the management of volume overload in HF patients. In addition to extracorporeal methods for relieving volume overload, peritoneal dialysis can be used as a viable alternative therapy for the short-term management of refractory congestive symptoms for patients in whom vascular access cannot be obtained, or for whom appropriate extracorporeal therapies are not available.
Prevention of Disease Progression ( TABLE 50.7 and Fig. 50.10 )
Drugs that interfere with the excessive activation of renin angiotensin-aldosterone system and the adrenergic nervous system can relieve the symptoms of HFrEF patients by stabilizing and/or reversing LV remodeling (see Chapter 47 ). In this regard ACEIs/ARBs and beta-blockers have emerged as cornerstones of modern HF therapy for patients with a depressed EF (see Fig. 50.10 ).
TABLE 50.7
Drugs for the Prevention and Treatment for Chronic Heart Failure
Modified from Mann DL. Heart Failure and Cor Pulmonale, In: Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine . 17th ed. New York: McGraw-Hill; 2007:1449.
| Initiating Dose | Maximal Dose | |
|---|---|---|
| Angiotensin-Converting Enzyme Inhibitors | ||
| Captopril | 6.25 mg 3 times | 50 mg 3 times |
| Enalapril | 2.5 mg twice | 10 mg twice |
| Lisinopril | 2.5–5.0 mg once | 20 mg once |
| Ramipril | 1.25–2.5 mg once | 10 mg once |
| Fosinopril | 5–10 mg once | 40 mg once |
| Quinapril | 5 mg twice | 40 mg twice |
| Trandolapril | 0.5 mg once | 4 mg once |
| Angiotensin Receptor Blockers | ||
| Valsartan | 40 mg twice | 160 mg twice |
| Candesartan | 4–8 mg once | 32 mg once |
| Losartan | 12.5–25 mg once | 50 mg once |
| Beta-Receptor Blockers | ||
| Carvedilol | 3.125 mg twice | 25 mg twice (50 mg twice if >85 kg) |
| Carvedilol-CR | 10 mg once | 80 mg once |
| Bisoprolol | 1.25 mg twice | 10 mg once |
| Metoprolol succinate CR | 12.5–25 mg qd | target dose 200 mg qd |
| Mineralocorticoid Receptor Antagonists | ||
| Spironolactone | 12.5–25 mg once | 25–50 mg once |
| Eplerenone | 25 mg once | 50 mg once |
| Other Agents | ||
| Combination of hydralazine/isosorbide dinitrate | 25 to 50 mg/10 mg 3 times | 100 mg/40 mg 3 times |
| Fixed dose of hydralazine/isosorbide dinitrate | 37.5 mg/20 mg (one tablet) 3 times | 75 mg/40 mg (two tablets) 3 times |
| Digoxin ∗ Ivabradine |
0.125 mg qd 5 mg twice daily |
≤0.375 mg/day ∗∗ 7.5 mg twice daily |
∗ Dosing should be based on ideal body weight, age, and renal function.
∗∗ Trough level should be 0.5 to 1 ng/mL though absolute levels have not established.
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