2013 ACCF/AHA Guideline for the Management of Heart Failure

A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

1.1 Methodology and Evidence Review

The recommendations listed in this document are, whenever possible, evidence based. An extensive evidence review was conducted through October 2011 and includes selected other references through April 2013. Searches were extended to studies, reviews, and other evidence conducted in human subjects and that were published in English from PubMed, EMBASE, Cochrane, Agency for Healthcare Research and Quality Reports, and other selected databases relevant to this guideline. Key search words included but were not limited to the following: heart failure, cardiomyopathy, quality of life, mortality, hospitalizations, prevention, biomarkers, hypertension, dyslipidemia, imaging, cardiac catheterization, endomyocardial biopsy, angiotensin-converting enzyme inhibitors, angiotensin-receptor antagonists/blockers, beta blockers, cardiac, cardiac resynchronization therapy, defibrillator, device-based therapy, implantable cardioverter-defibrillator, device implantation, medical therapy, acute decompensated heart failure, preserved ejection fraction, terminal care and transplantation, quality measures, and performance measures. Additionally, the committee reviewed documents related to the subject matter previously published by the ACCF and AHA. References selected and published in this document are representative and not all-inclusive.

To provide clinicians with a representative evidence base, whenever deemed appropriate or when published, the absolute risk difference and number needed to treat or harm are provided in the guideline (within tables), along with confidence intervals and data related to the relative treatment effects such as odds ratio, relative risk, hazard ratio, and incidence rate ratio.

1.2 Organization of the Writing Committee

The committee was composed of physicians and a nurse with broad expertise in the evaluation, care, and management of patients with heart failure (HF). The authors included general cardiologists, HF and transplant specialists, electrophysiologists, general internists, and physicians with methodological expertise. The committee included representatives from the ACCF, AHA, American Academy of Family Physicians, American College of Chest Physicians, American College of Physicians, Heart Rhythm Society, and International Society for Heart and Lung Transplantation.

1.3 Document Review and Approval

This document was reviewed by 2 official reviewers each nominated by both the ACCF and the AHA, as well as 1 to 2 reviewers each from the American Academy of Family Physicians, American College of Chest Physicians, Heart Rhythm Society, and International Society for Heart and Lung Transplantation, as well as 32 individual content reviewers (including members of the ACCF Adult Congenital and Pediatric Cardiology Council, ACCF Cardiovascular Team Council, ACCF Council on Cardiovascular Care for Older Adults, ACCF Electrophysiology Committee, ACCF Heart Failure and Transplant Council, ACCF Imaging Council, ACCF Prevention Committee, ACCF Surgeons’ Scientific Council, and ACCF Task Force on Appropriate Use Criteria). All information on reviewers’ RWI was distributed to the writing committee and is published in this document (Appendix 2).

This document was approved for publication by the governing bodies of the ACCF and AHA and endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, American College of Chest Physicians, Heart Rhythm Society, and International Society for Heart and Lung Transplantation.

1.4 Scope of This Guideline With Reference to Other Relevant Guidelines or Statements

This guideline covers multiple management issues for the adult patient with HF. Although there is an abundance of evidence addressing HF, for many important clinical considerations, this writing committee was unable to identify sufficient data to properly inform a recommendation. The writing committee actively worked to reduce the number of LOE “C” recommendations, especially for Class I−recommended therapies. Despite these limitations, it is apparent that much can be done for HF. Adherence to the clinical practice guidelines herein reproduced should lead to improved patient outcomes.

Although of increasing importance, HF in children and congenital heart lesions in adults are not specifically addressed in this guideline. The reader is referred to publically available resources to address questions in these areas. However, this guideline does address HF with preserved ejection fraction (EF) in more detail and similarly revisits hospitalized HF. Additional areas of renewed interest are in stage D HF, palliative care, transition of care, and quality of care for HF. Certain management strategies appropriate for the patient at risk for HF or already affected by HF are also reviewed in numerous relevant clinical practice guidelines and scientific statements published by the ACCF/AHA Task Force on Practice Guidelines, AHA, ACCF Task Force on Appropriate Use Criteria, European Society of Cardiology, Heart Failure Society of America, and the National Heart, Lung, and Blood Institute. The writing committee saw no need to reiterate the recommendations contained in those guidelines and chose to harmonize recommendations when appropriate and eliminate discrepancies. This is especially the case for device-based therapeutics, where complete alignment between the HF guideline and the device-based therapy guideline was deemed imperative (4). Some recommendations from earlier guidelines have been updated as warranted by new evidence or a better understanding of earlier evidence, whereas others that were no longer accurate or relevant or which were overlapping were modified; recommendations from previous guidelines that were similar or redundant were eliminated or consolidated when possible.

The present document recommends a combination of lifestyle modifications and medications that constitute GDMT. GDMT is specifically referenced in the recommendations for the treatment of HF (Section 7.3.2). Both for GDMT and other recommended drug treatment regimens, the reader is advised to confirm dosages with product insert material and to evaluate carefully for contraindications and drug-drug interactions. Table 2 is a list of documents deemed pertinent to this effort and is intended for use as a resource; it obviates the need to repeat already extant guideline recommendations. Additional other HF guideline statements are highlighted as well for the purpose of comparison and completeness.

2.1 HF With Reduced EF (HFrEF)

In approximately half of patients with HFrEF, variable degrees of LV enlargement may accompany HFrEF (36,37). The definition of HFrEF has varied, with guidelines of left ventricular ejection fraction (LVEF) ≤35%, <40%, and ≤40% (18,19,38). Randomized controlled trials (RCTs) in patients with HF have mainly enrolled patients with HFrEF with an EF ≤35% or ≤40%, and it is only in these patients that efficacious therapies have been demonstrated to date. For the present guideline, HFrEF is defined as the clinical diagnosis of HF and EF ≤40%. Those with LV systolic dysfunction commonly have elements of diastolic dysfunction as well (39). Although coronary artery disease (CAD) with antecedent myocardial infarction (MI) is a major cause of HFrEF, many other risk factors (Section 4.6) may lead to LV enlargement and HFrEF.

2.2 HF With Preserved EF (HFpEF)

In patients with clinical HF, studies estimate that the prevalence of HFpEF is approximately 50% (range 40% to 71%) (40). These estimates vary largely because of the differing EF cut-off criteria and challenges in diagnostic criteria for HFpEF. HFpEF has been variably classified as EF >40%, >45%, >50%, and ≥55%. Because some of these patients do not have entirely normal EF but also do not have major reduction in systolic function, the term preserved EF has been used. Patients with an EF in the range of 40% to 50% represent an intermediate group. These patients are often treated for underlying risk factors and comorbidities and with GDMT similar to that used in patients with HFrEF. Several criteria have been proposed to define the syndrome of HFpEF. These include a) clinical signs or symptoms of HF; b) evidence of preserved or normal LVEF; and c) evidence of abnormal LV diastolic dysfunction that can be determined by Doppler echocardiography or cardiac catheterization (41). The diagnosis of HFpEF is more challenging than the diagnosis of HFrEF because it is largely one of excluding other potential noncardiac causes of symptoms suggestive of HF. Studies have suggested that the incidence of HFpEF is increasing and that a greater portion of patients hospitalized with HF have HFpEF (42). In the general population, patients with HFpEF are usually older women with a history of hypertension. Obesity, CAD, diabetes mellitus, atrial fibrillation (AF), and hyperlipidemia are also highly prevalent in HFpEF in population-based studies and registries (40,43). Despite these associated cardiovascular risk factors, hypertension remains the most important cause of HFpEF, with a prevalence of 60% to 89% from large controlled trials, epidemiological studies, and HF registries (44). It has been recognized that a subset of patients with HFpEF previously had HFrEF (45). These patients with improvement or recovery in EF may be clinically distinct from those with persistently preserved or reduced EF. Further research is needed to better characterize these patients.

See Online Data Supplement 1 for additional data on HFpEF.

4.1 Mortality

Although survival has improved, the absolute mortality rates for HF remain approximately 50% within 5 years of diagnosis (53,59). In the ARIC study, the 30-day, 1-year, and 5-year case fatality rates after hospitalization for HF were 10.4%, 22%, and 42.3%, respectively (58). In another population cohort study with 5-year mortality data, survival for stage A, B, C, and D HF was 97%, 96%, 75%, and 20%, respectively (47). Thirty-day postadmission mortality rates decreased from 12.6% to 10.8% from 1993 to 2005; however, this was due to lower in-hospital death rates. Postdischarge mortality actually increased from 4.3% to 6.4% during the same time frame (60). These observed temporal trends in HF survival are primarily restricted to patients with reduced EF and are not seen in those with preserved EF (40).

See Online Data Supplement 3 for additional data on mortality.

4.2 Hospitalizations

HF is the primary diagnosis in >1 million hospitalizations annually (51). Patients hospitalized for HF are at high risk for all-cause rehospitalization, with a 1-month readmission rate of 25% (61). In 2013, physician office visits for HF cost $1.8 billion. The total cost of HF care in the United States exceeds $30 billion annually, with over half of these costs spent on hospitalizations (51).

4.3 Asymptomatic LV Dysfunction

The prevalence of asymptomatic LV systolic or diastolic dysfunction ranges from 6% to 21% and increases with age (62–64). In the Left Ventricular Dysfunction Prevention study, participants with untreated asymptomatic LV dysfunction had a 10% risk for developing HF symptoms and an 8% risk of death or HF hospitalization annually (65). In a community-based population, asymptomatic mild LV diastolic dysfunction was seen in 21% and moderate or severe diastolic dysfunction in 7%, and both were associated with an increased risk of symptomatic HF and mortality (64).

4.4 Health-Related Quality of Life and Functional Status

HF significantly decreases health-related quality of life (HRQOL), especially in the areas of physical functioning and vitality (66,67). Lack of improvement in HRQOL after discharge from the hospital is a powerful predictor of rehospitalization and mortality (68,69). Women with HF have consistently been found to have poorer HRQOL than men (67,70). Ethnic differences also have been found, with Mexican Hispanics reporting better HRQOL than other ethnic groups in the United States (71). Other determinants of poor HRQOL include depression, younger age, higher body mass index (BMI), greater symptom burden, lower systolic blood pressure, sleep apnea, low perceived control, and uncertainty about prognosis (70,72–76). Memory problems may also contribute to poor HRQOL (76).

Pharmacological therapy is not a consistent determinant of HRQOL; therapies such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) improve HRQOL only modestly or delay the progressive worsening of HRQOL in HF (77). At present, the only therapies shown to improve HRQOL are cardiac resynchronization therapy (CRT) (78) and certain disease management and educational approaches (79–82). Self-care and exercise may improve HRQOL, but the results of studies evaluating these interventions are mixed (83–86). Throughout this guideline we refer to meaningful survival as a state in which HRQOL is satisfactory to the patient.

See Online Data Supplement 4 for additional data on HRQOL and functional capacity.

4.5 Economic Burden of HF

In 1 in 9 deaths in the United States, HF is mentioned on the death certificate. The number of deaths with any mention of HF was as high in 2006 as it was in 1995 (51). Approximately 7% of all cardiovascular deaths are due to HF.

As previously noted, in 2013, HF costs in the United States exceeded $30 billion (51). This total includes the cost of healthcare services, medications, and lost productivity. The mean cost of HF-related hospitalizations was $23,077 per patient and was higher when HF was a secondary rather than the primary diagnosis. Among patients with HF in 1 large population study, hospitalizations were common after HF diagnosis, with 83% of patients hospitalized at least once and 43% hospitalized at least 4 times. More than half of the hospitalizations were related to noncardiovascular causes (87–89).

4.6 Important Risk Factors for HF (Hypertension, Diabetes Mellitus, Metabolic Syndrome, and Atherosclerotic Disease)

Many conditions or comorbidities are associated with an increased propensity for structural heart disease. The expedient identification and treatment of these comorbid conditions may forestall the onset of HF (14,27,90). A list of the important documents that codify treatment for these concomitant conditions appears in Table 2.

5.1 Dilated Cardiomyopathies

5.2 Familial Cardiomyopathies

Increasingly, it is recognized that many (20% to 35%) patients with an idiopathic DCM have a familial cardiomyopathy (defined as 2 closely related family members who meet the criteria for idiopathic DCM) (118,119). Consideration of familial cardiomyopathies includes the increasingly important discovery of noncompaction cardiomyopathies. Advances in technology permitting high-throughput sequencing and genotyping at reduced costs have brought genetic screening to the clinical arena. For further information on this topic, the reader is referred to published guidelines, position statements, and expert consensus statements (118,120–123) (Table 5).

5.3 Endocrine and Metabolic Causes of Cardiomyopathy

5.4 Toxic Cardiomyopathy

5.5 Tachycardia-Induced Cardiomyopathy

Tachycardia-induced cardiomyopathy is a reversible cause of HF characterized by LV myocardial dysfunction caused by increased ventricular rate. The degree of dysfunction correlates with the duration and rate of the tachyarrhythmia. Virtually any supraventricular tachycardia with a rapid ventricular response may induce cardiomyopathy. Ventricular arrhythmias, including frequent premature ventricular complexes, may also induce cardiomyopathy. Maintenance of sinus rhythm or control of ventricular rate is critical to treating patients with tachycardia-induced cardiomyopathy (154). Reversibility of the cardiomyopathy with treatment of the arrhythmia is the rule, although this may not be complete in all cases. The underlying mechanisms for this are not well understood.

Ventricular pacing at high rates may cause cardiomyopathy. Additionally, right ventricular pacing alone may exacerbate HF symptoms, increase hospitalization for HF, and increase mortality (155,156). Use of CRT in patients with a conduction delay due to pacing may result in improved LV function and functional capacity.

5.6 Myocarditis and Cardiomyopathies Due to Inflammation

5.7 Inflammation-Induced Cardiomyopathy: Noninfectious Causes

5.8 Peripartum Cardiomyopathy

Peripartum cardiomyopathy is a disease of unknown cause in which LV dysfunction occurs during the last trimester of pregnancy or the early puerperium. It is reported in 1:1300 to 1:4000 live births (174). Risk factors for peripartum cardiomyopathy include advanced maternal age, multiparity, African descent, and long-term tocolysis. Although its etiology remains unknown, most theories have focused on hemodynamic and immunologic causes (174). The prognosis of peripartum cardiomyopathy is related to the recovery of ventricular function. Significant improvement in myocardial function is seen in 30% to 50% of patients in the first 6 months after presentation (174). However, for those patients who do not recover to normal or near-normal function, the prognosis is similar to other forms of DCM (175). Cardiomegaly that persists for >4 to 6 months after diagnosis indicates a poor prognosis, with a 50% mortality rate at 6 years. Subsequent pregnancy in women with a history of peripartum cardiomyopathy may be associated with a further decrease in LV function and can result in clinical deterioration, including death. However, if ventricular function has normalized in women with a history of peripartum cardiomyopathy, the risk may be less (174). There is an increased risk of venous thromboembolism, and anticoagulation is recommended, especially if ventricular dysfunction is persistent.

5.9 Cardiomyopathy Caused by Iron Overload

Iron overload cardiomyopathy manifests itself as systolic or diastolic dysfunction secondary to increased deposition of iron in the heart and occurs with common genetic disorders such as primary hemochromatosis or with lifetime transfusion requirements as seen in beta-thalassemia major (176). Hereditary hemochromatosis, an autosomal recessive disorder, is the most common hereditary disease of Northern Europeans, with a prevalence of approximately 5 per 1,000. The actuarial survival rates of persons who are homozygous for the mutation of the hemochromatosis gene C282Y have been reported to be 95%, 93%, and 66%, at 5, 10, and 20 years, respectively (177). Similarly, in patients with thalassemia major, cardiac failure is one of the most frequent causes of death. Chelation therapy, including newer forms of oral chelators, such as deferoxamine, and phlebotomy, have dramatically improved the outcome of hemochromatosis, and the roles of gene therapy, hepcidin, and calcium channel blockers are being actively investigated (178).

5.10 Amyloidosis

Cardiac amyloidosis involves the deposition of insoluble proteins as fibrils in the heart, resulting in HF. Primary or AL amyloidosis (monoclonal kappa or lambda light chains), secondary amyloidosis (protein A), familial TTR amyloidosis (mutant transthyretin), dialysis-associated amyloidosis (beta-2-microglobulin), or senile TTR amyloidosis (wild-type transthyretin) can affect the heart, but cardiac involvement is primarily encountered in AL and TTR amyloidosis (179). The disease can be rapidly progressive, and in patients with ventricular septum thickness >15 mm, LVEF <40%, and symptoms of HF, median survival may be <6 months (180). Cardiac biomarkers (e.g., B-type natriuretic peptide [BNP], cardiac troponin) have been reported to predict response and progression of disease and survival (181). Three percent to 4% of African Americans carry an amyloidogenic allele of the human serum protein transthyretin (TTR V122I), which appears to increase risk for cardiac amyloid deposition after 65 years of age (182).

5.11 Cardiac Sarcoidosis

Cardiac sarcoidosis is an underdiagnosed disease that may affect as many as 25% of patients with systemic sarcoidosis. Although most commonly recognized in patients with other manifestations of sarcoidosis, cardiac involvement may occur in isolation and go undetected. Cardiac sarcoidosis may present as asymptomatic LV dysfunction, HF, atrioventricular block, atrial or ventricular arrhythmia, and SCD (183). Although untested in clinical trials, early use of high-dose steroid therapy may halt or reverse cardiac damage (184). Cardiac magnetic resonance and cardiac positron emission tomographic scanning can identify cardiac involvement with patchy areas of myocardial inflammation and fibrosis. In the setting of ventricular tachyarrhythmia, patients may require placement of an implantable cardioverter-defibrillator (ICD) for primary prevention of SCD (185).

5.12 Stress (Takotsubo) Cardiomyopathy

Stress cardiomyopathy is characterized by acute reversible LV dysfunction in the absence of significant CAD, triggered by acute emotional or physical stress (23). This phenomenon is identified by a distinctive pattern of “apical ballooning,” first described in Japan as takotsubo, and often affects postmenopausal women (186). A majority of patients have a clinical presentation similar to that of acute coronary syndrome (ACS) and may have transiently elevated cardiac enzymes.

6.1 Clinical Evaluation

6.2 Diagnostic Tests: Recommendations

• 1. Initial laboratory evaluation of patients presenting with HF should include complete blood count, urinalysis, serum electrolytes (including calcium and magnesium), blood urea nitrogen, serum creatinine, glucose, fasting lipid profile, liver function tests, and thyroid-stimulating hormone. (Level of Evidence: C)

• 2. Serial monitoring, when indicated, should include serum electrolytes and renal function. (Level of Evidence: C)

• 3. A 12-lead ECG should be performed initially on all patients presenting with HF. (Level of Evidence: C)

• 1. Screening for hemochromatosis or HIV is reasonable in selected patients who present with HF (216). (Level of Evidence: C)

• 2. Diagnostic tests for rheumatologic diseases, amyloidosis, or pheochromocytoma are reasonable in patients presenting with HF in whom there is a clinical suspicion of these diseases. (Level of Evidence: C)

6.3 Biomarkers: Recommendations

6.4 Noninvasive Cardiac Imaging: Recommendations

See Table 10 for a summary of recommendations from this section.

• 1. Patients with suspected or new-onset HF, or those presenting with acute decompensated HF, should undergo a chest x-ray to assess heart size and pulmonary congestion and to detect alternative cardiac, pulmonary, and other diseases that may cause or contribute to the patient’s symptoms. (Level of Evidence: C)

• 2. A 2-dimensional echocardiogram with Doppler should be performed during initial evaluation of patients presenting with HF to assess ventricular function, size, wall thickness, wall motion, and valve function. (Level of Evidence: C)

• 3. Repeat measurement of EF and measurement of the severity of structural remodeling are useful to provide information in patients with HF who have had a significant change in clinical status; who have experienced or recovered from a clinical event; or who have received treatment, including GDMT, that might have had a significant effect on cardiac function; or who may be candidates for device therapy. (Level of Evidence: C)

• 1. Noninvasive imaging to detect myocardial ischemia and viability is reasonable in patients presenting with de novo HF, who have known CAD and no angina, unless the patient is not eligible for revascularization of any kind. (Level of Evidence: C)

• 2. Viability assessment is reasonable in select situations when planning revascularization in HF patients with CAD (281–285). (Level of Evidence: B)

• 3. Radionuclide ventriculography or magnetic resonance imaging can be useful to assess LVEF and volume when echocardiography is inadequate. (Level of Evidence: C)

• 4. Magnetic resonance imaging is reasonable when assessing myocardial infiltrative processes or scar burden (286–288). (Level of Evidence: B)

• 1. Routine repeat measurement of LV function assessment in the absence of clinical status change or treatment interventions should not be performed (289,290). (Level of Evidence: B)

The chest x-ray is important for the evaluation of patients presenting with signs and symptoms of HF because it assesses cardiomegaly and pulmonary congestion and may reveal alternative causes, cardiopulmonary or otherwise, of the patient’s symptoms. Apart from congestion, however, other findings on chest x-ray are associated with HF only in the context of clinical presentation. Cardiomegaly may be absent in HF. A chest x-ray may also show other cardiac chamber enlargement, increased pulmonary venous pressure, interstitial or alveolar edema, valvular or pericardial calcification, or coexisting thoracic diseases. Considering its low sensitivity and specificity, the chest x-ray should not be the sole determinant of the specific cause of HF. Moreover, a supine chest x-ray has limited value in acute decompensated HF.

Although a complete history and physical examination are important first steps, the most useful diagnostic test in the evaluation of patients with or at risk for HF (e.g., postacute MI) is a comprehensive 2-dimensional echocardiogram; coupled with Doppler flow studies, the transthoracic echocardiogram can identify abnormalities of myocardium, heart valves, and pericardium. Echocardiography can reveal subclinical HF and predict risk of subsequent events (291–295). Use of echocardiograms in patients with suspected HF improves disease identification and provision of appropriate medical care (296).

Echocardiographic evaluation should address whether LVEF is reduced, LV structure is abnormal, and other structural abnormalities are present that could account for the clinical presentation. This information should be quantified, including numerical estimates of EF measurement, ventricular dimensions, wall thickness, calculations of ventricular volumes, and evaluation of chamber geometry and regional wall motion. Documentation of LVEF is an HF quality-of-care performance measure (297). Right ventricular size and function as well as atrial size and dimensions should also be measured. All valves should be evaluated for anatomic and flow abnormalities. Secondary changes, particularly the severity of mitral and tricuspid valve insufficiency, should be determined. Noninvasive hemodynamic data constitute important additional information. Mitral valve inflow pattern, pulmonary venous inflow pattern, and mitral annular velocity provide data about LV filling and left atrial pressure. The tricuspid valve regurgitant gradient, coupled with measurement of inferior vena cava diameter and its response during respiration, provides estimates of systolic pulmonary artery pressure and central venous pressure. Many of these abnormalities are prognostically important and can be present without manifest HF.

Serial echocardiographic evaluations are useful because evidence of cardiac reverse remodeling can provide important information in patients who have had a change in clinical status or have experienced or recovered from an event or treatment that affects cardiac function. However, the routine repeat assessment of ventricular function in the absence of changing clinical status or a change in treatment intervention is not indicated.

The preference for echocardiography as an imaging modality is due to its widespread availability and lack of ionizing radiation; however, other imaging modalities may be of use. Magnetic resonance imaging assesses LV volume and EF measurements at least as accurately as echocardiography. However, additional information about myocardial perfusion, viability, and fibrosis from magnetic resonance imaging can help identify HF etiology and assess prognosis (298). Magnetic resonance imaging provides high anatomical resolution of all aspects of the heart and surrounding structure, leading to its recommended use in known or suspected congenital heart diseases (5). Cardiac computed tomography can also provide accurate assessment of cardiac structure and function, including the coronary arteries (299). An advantage of cardiac computed tomography over echocardiography may be its ability to characterize the myocardium, but studies have yet to demonstrate the importance of this factor. Reports of cardiac computed tomography in patients with suspected HF are limited. Furthermore, both cardiac computed tomography and magnetic resonance imaging lose accuracy with high heart rates. Radionuclide ventriculography may also be used for evaluation of cardiac function when other tests are unavailable or inadequate. However, as a planar technique, radionuclide ventriculography cannot directly assess valvular structure, function, or ventricular wall thickness; it may be more useful for assessing LV volumes in patients with significant baseline wall motion abnormalities or distorted geometry. Ventriculography is highly reproducible (300). Single photon emission computed tomography or positron emission tomography scans are not primarily used to determine LV systolic global and regional function unless these parameters are quantified from the resultant images during myocardial perfusion and/or viability assessment (301,302). Candidates for coronary revascularization who present with a high suspicion for obstructive CAD should undergo coronary angiography. Stress nuclear imaging or echocardiography may be an acceptable option for assessing ischemia in patients presenting with HF who have known CAD and no angina unless they are ineligible for revascularization (303). Although the results of the STICH (Surgical Treatment for Ischemic Heart Failure) trial have cast doubt on the role of myocardial viability assessment to determine the mode of therapy (304), the data are nevertheless predictive of a positive outcome. When these data are taken into consideration with multiple previous studies demonstrating the usefulness of this approach (281–285), it becomes reasonable to recommend viability assessment when treating patients with HFrEF who have known CAD (14).

See Online Data Supplement 9 for additional data on imaging−echocardiography.

6.5 Invasive Evaluation: Recommendations

See Table 11 for a summary of recommendations from this section.

• 1. Invasive hemodynamic monitoring with a pulmonary artery catheter should be performed to guide therapy in patients who have respiratory distress or clinical evidence of impaired perfusion in whom the adequacy or excess of intracardiac filling pressures cannot be determined from clinical assessment. (Level of Evidence: C)

• 1. Invasive hemodynamic monitoring can be useful for carefully selected patients with acute HF who have persistent symptoms despite empiric adjustment of standard therapies and

  • a. whose fluid status, perfusion, or systemic or pulmonary vascular resistance is uncertain;

  • b. whose systolic pressure remains low, or is associated with symptoms, despite initial therapy;

  • c. whose renal function is worsening with therapy;

  • d. who require parenteral vasoactive agents; or

  • e. who may need consideration for MCS or transplantation. (Level of Evidence: C)

• 2. When ischemia may be contributing to HF, coronary arteriography is reasonable for patients eligible for revascularization. (Level of Evidence: C)

• 3. Endomyocardial biopsy can be useful in patients presenting with HF when a specific diagnosis is suspected that would influence therapy. (Level of Evidence: C)

• 1. Routine use of invasive hemodynamic monitoring is not recommended in normotensive patients with acute decompensated HF and congestion with symptomatic response to diuretics and vasodilators (305). (Level of Evidence: B)

• 1. Endomyocardial biopsy should not be performed in the routine evaluation of patients with HF. (Level of Evidence: C)

7.1 Stage A: Recommendations

• 1. Hypertension and lipid disorders should be controlled in accordance with contemporary guidelines to lower the risk of HF (27,94,311–314). (Level of Evidence: A)

• 2. Other conditions that may lead to or contribute to HF, such as obesity, diabetes mellitus, tobacco use, and known cardiotoxic agents, should be controlled or avoided. (Level of Evidence: C)

7.2 Stage B: Recommendations

See Table 12 for a summary of recommendations from this section.

• 1. In all patients with a recent or remote history of MI or ACS and reduced EF, ACE inhibitors should be used to prevent symptomatic HF and reduce mortality (342–344). In patients intolerant of ACE inhibitors, ARBs are appropriate unless contraindicated (314,345). (Level of Evidence: A)

• 2. In all patients with a recent or remote history of MI or ACS and reduced EF, evidence-based beta blockers should be used to reduce mortality (346–348). (Level of Evidence: B)

• 3. In all patients with a recent or remote history of MI or ACS, statins should be used to prevent symptomatic HF and cardiovascular events (104,349–354). (Level of Evidence: A)

• 4. In patients with structural cardiac abnormalities, including LV hypertrophy, in the absence of a history of MI or ACS, blood pressure should be controlled in accordance with clinical practice guidelines for hypertension to prevent symptomatic HF (27,94,311–313). (Level of Evidence: A)

• 5. ACE inhibitors should be used in all patients with a reduced EF to prevent symptomatic HF, even if they do not have a history of MI (65,344). (Level of Evidence: A)

• 6. Beta blockers should be used in all patients with a reduced EF to prevent symptomatic HF, even if they do not have a history of MI. (Level of Evidence: C)

• 1. To prevent sudden death, placement of an ICD is reasonable in patients with asymptomatic ischemic cardiomyopathy who are at least 40 days post-MI, have an LVEF of 30% or less, are on appropriate medical therapy, and have reasonable expectation of survival with a good functional status for more than 1 year (355). (Level of Evidence: B)

• 1. Nondihydropyridine calcium channel blockers with negative inotropic effects may be harmful in asymptomatic patients with low LVEF and no symptoms of HF after MI. (Level of Evidence: C)

Patients with reduced LVEF may not have HF symptoms and are most often identified during an evaluation for another disorder (e.g., abnormal heart sounds, abnormal ECG, abnormal chest x-ray, hypertension or hypotension, an arrhythmia, acute MI, or pulmonary or systemic thromboembolic event). However, the cost-effectiveness of routine periodic population screening for asymptomatic reduced LVEF is not recommended at this time. Echocardiographic evaluation should be performed in selected patients who are at high risk of reduced LVEF (e.g., those with a strong family history of cardiomyopathy, long-standing hypertension, previous MI, or those receiving cardiotoxic therapies). In addition, it should be acknowledged that many adults may have asymptomatic valvular abnormalities or congenital heart lesions that if unrecognized could lead to the development of clinical HF. Although these asymptomatic patients are in stage B as well, the management of valvular and congenital heart disease is beyond the scope of this guideline.

7.3 Stage C

See Online Data Supplement 13 for additional data on stage C HF.

7.3.2 Pharmacological Treatment for Stage C HFrEF: Recommendations

Class I

• 1. Measures listed as Class I recommendations for patients in stages A and B are recommended where appropriate for patients in stage C. (Levels of Evidence: A, B, and C as appropriate)

• 2. GDMT as depicted in Figure 1 should be the mainstay of pharmacological therapy for HFrEF (108,343,345,346,412–426). (Level of Evidence: A)

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Figure 1

Stage C HFrEF: evidence-based, guideline-directed medical therapy. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; HFrEF, heart failure with reduced ejection fraction; Hydral-Nitrates, hydralazine and isosorbide dinitrate; LOE, Level of Evidence; and NYHA, New York Heart Association.

7.3.2.1 Diuretics: Recommendation

Class I

• 1. Diuretics are recommended in patients with HFrEF who have evidence of fluid retention, unless contraindicated, to improve symptoms. (Level of Evidence: C)

Diuretics inhibit the reabsorption of sodium or chloride at specific sites in the renal tubules. Bumetanide, furosemide, and torsemide act at the loop of Henle (thus, the term loop diuretics), whereas thiazides, metolazone, and potassium-sparing agents (e.g., spironolactone) act in the distal portion of the tubule (427,428). Loop diuretics have emerged as the preferred diuretic agents for use in most patients with HF. Thiazide diuretics may be considered in hypertensive patients with HF and mild fluid retention because they confer more persistent antihypertensive effects.

Controlled trials have demonstrated the ability of diuretic drugs to increase urinary sodium excretion and decrease physical signs of fluid retention in patients with HF (429,430). In intermediate-term studies, diuretics have been shown to improve symptoms and exercise tolerance in patients with HF (431–433); however, diuretic effects on morbidity and mortality are not known. Diuretics are the only drugs used for the treatment of HF that can adequately control the fluid retention of HF. Appropriate use of diuretics is a key element in the success of other drugs used for the treatment of HF. The use of inappropriately low doses of diuretics will result in fluid retention. Conversely, the use of inappropriately high doses of diuretics will lead to volume contraction, which can increase the risk of hypotension and renal insufficiency.

7.3.2.1.1 Diuretics: Selection of Patients

Diuretics should be prescribed to all patients who have evidence of, and to most patients with a prior history of, fluid retention. Diuretics should generally be combined with an ACE inhibitor, beta blocker, and aldosterone antagonist. Few patients with HF will be able to maintain target weight without the use of diuretics.

7.3.2.1.2 Diuretics: Initiation and Maintenance

The most commonly used loop diuretic for the treatment of HF is furosemide, but some patients respond more favorably to other agents in this category (e.g., bumetanide, torsemide) because of their increased oral bioavailability (434,435). Table 14 lists oral diuretics recommended for use in the treatment of chronic HF. In outpatients with HF, diuretic therapy is commonly initiated with low doses, and the dose is increased until urine output increases and weight decreases, generally by 0.5 to 1.0 kg daily. Further increases in the dose or frequency (i.e., twice-daily dosing) of diuretic administration may be required to maintain an active diuresis and sustain weight loss. The ultimate goal of diuretic treatment is to eliminate clinical evidence of fluid retention. Diuretics are generally combined with moderate dietary sodium restriction. Once fluid retention has resolved, treatment with the diuretic should be maintained in some patients to prevent the recurrence of volume overload. Patients are commonly prescribed a fixed dose of diuretic, but the dose of these drugs frequently may need adjustment. In many cases, this adjustment can be accomplished by having patients record their weight each day and adjusting the diuretic dosage if weight increases or decreases beyond a specified range. Patients may become unresponsive to high doses of diuretic drugs if they consume large amounts of dietary sodium, are taking agents that can block the effects of diuretics (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], including cyclooxygenase-2 inhibitors) (436–438) or have a significant impairment of renal function or perfusion (434). Diuretic resistance can generally be overcome by the intravenous administration of diuretics (including the use of continuous infusions) (439) or combination of different diuretic classes (e.g., metolazone with a loop diuretic) (440–443).

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Table 14

Oral Diuretics Recommended for Use in the Treatment of Chronic HF

7.3.2.1.3 Diuretics: Risks of Treatment

The principal adverse effects of diuretics include electrolyte and fluid depletion, as well as hypotension and azotemia. Diuretics can cause the depletion of potassium and magnesium, which can predispose patients to serious cardiac arrhythmias (444). The risk of electrolyte depletion is markedly enhanced when 2 diuretics are used in combination.

See Online Data Supplement 17 for additional data on diuretics.

7.3.2.2 ACE Inhibitors: Recommendation

Class I

• 1. ACE inhibitors are recommended in patients with HFrEF and current or prior symptoms, unless contraindicated, to reduce morbidity and mortality (343,412–414). (Level of Evidence: A)

7.3.2.2.1 ACE Inhibitors: Selection of Patients

ACE inhibitors can reduce the risk of death and reduce hospitalization in HFrEF. The benefits of ACE inhibition were seen in patients with mild, moderate, or severe symptoms of HF and in patients with or without CAD. ACE inhibitors should be prescribed to all patients with HFrEF. Unless there is a contraindication, ACE inhibitors are used together with a beta blocker. Patients should not be given an ACE inhibitor if they have experienced life-threatening adverse reactions (i.e., angioedema) during previous medication exposure or if they are pregnant or plan to become pregnant. Clinicians should prescribe an ACE inhibitor with caution if the patient has very low systemic blood pressures (systolic blood pressure <80 mm Hg), markedly increased serum levels of creatinine (>3 mg/dL), bilateral renal artery stenosis, or elevated levels of serum potassium (>5.0 mEq/L).

7.3.2.2.2 ACE Inhibitors: Initiation and Maintenance

The available data suggest that there are no differences among available ACE inhibitors in their effects on symptoms or survival (414). Treatment with an ACE inhibitor should be initiated at low doses (Table 15), followed by gradual dose increments if lower doses have been well tolerated. Renal function and serum potassium should be assessed within 1 to 2 weeks of initiation of therapy and periodically thereafter, especially in patients with preexisting hypotension, hyponatremia, diabetes mellitus, azotemia, or in those taking potassium supplements. In controlled clinical trials that were designed to evaluate survival, the dose of the ACE inhibitor was not determined by a patient’s therapeutic response but was increased until the predetermined target dose was reached (343,413,414). Clinicians should attempt to use doses that have been shown to reduce the risk of cardiovascular events in clinical trials. If these target doses of an ACE inhibitor cannot be used or are poorly tolerated, intermediate doses should be used with the expectation that there are likely to be only small differences in efficacy between low and high doses. Abrupt withdrawal of treatment with an ACE inhibitor can lead to clinical deterioration and should be avoided.

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Table 15

Drugs Commonly Used for Stage C HFrEF

7.3.2.2.3 ACE Inhibitors: Risks of Treatment

The majority of the adverse reactions of ACE inhibitors can be attributed to the 2 principal pharmacological actions of these drugs: those related to angiotensin suppression and those related to kinin potentiation. Other types of adverse effects may also occur (e.g., rash and taste disturbances). Up to 20% of patients will experience an ACE inhibitor–induced cough. With the use of ACE inhibitors, particular care should be given to the patient’s volume status, renal function, and concomitant medications (Sections 7.3.2.1 and 7.3.2.9). However, most HF patients (85% to 90%) can tolerate these drugs.

See Online Data Supplement 18 for additional data on ACE inhibitors.

7.3.2.3 ARBs: Recommendations

Class I

• 1. ARBs are recommended in patients with HFrEF with current or prior symptoms who are ACE inhibitor intolerant, unless contraindicated, to reduce morbidity and mortality (108,345,415,450). (Level of Evidence: A)

Class IIa

• 1. ARBs are reasonable to reduce morbidity and mortality as alternatives to ACE inhibitors as first-line therapy for patients with HFrEF, especially for patients already taking ARBs for other indications, unless contraindicated (451–456). (Level of Evidence: A)

Class IIb

• 1. Addition of an ARB may be considered in persistently symptomatic patients with HFrEF who are already being treated with an ACE inhibitor and a beta blocker in whom an aldosterone antagonist is not indicated or tolerated (420,457). (Level of Evidence: A)

Class III: Harm

• 1. Routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is potentially harmful for patients with HFrEF. (Level of Evidence: C)

ARBs were developed with the rationale that a) angiotensin II production continues in the presence of ACE inhibition, driven through alternative enzyme pathways and b) interference with the renin-angiotensin system without inhibition of kininase would produce all of the benefits of ACE inhibitors while minimizing the risk of adverse reactions to them. However, it is now known that some of the benefits of ACE inhibitors may be related to the accumulation of kinins rather than to the suppression of angiotensin II formation, whereas some of the adverse effects of ACE inhibitors in HF are related to the suppression of angiotensin II formation.

In several placebo-controlled studies, long-term therapy with ARBs produced hemodynamic, neurohormonal, and clinical effects consistent with those expected after interference with the renin-angiotensin system. Reduced hospitalization and mortality have been demonstrated. ACE inhibitors remain the first choice for inhibition of the renin-angiotensin system in systolic HF, but ARBs can now be considered a reasonable alternative.

7.3.2.3.1 ARBs: Selection of Patients

ARBs are used in patients with HFrEF who are ACE inhibitor intolerant; an ACE-inhibition intolerance primarily related to cough is the most common indication. In addition, an ARB may be used as an alternative to an ACE inhibitor in patients who are already taking an ARB for another reason, such as hypertension, and who subsequently develop HF. Angioedema occurs in <1% of patients who take an ACE inhibitor, but it occurs more frequently in blacks. Because its occurrence may be life-threatening, clinical suspicion of this reaction justifies the subsequent avoidance of all ACE inhibitors for the lifetime of the patient. ACE inhibitors should not be initiated in any patient with a history of angioedema. Although ARBs may be considered as alternative therapy for patients who have developed angioedema while taking an ACE inhibitor, there are some patients who have also developed angioedema with ARBs, and caution is advised when substituting an ARB in a patient who has had angioedema associated with use of an ACE inhibitor (458–461).

7.3.2.3.2 ARBs: Initiation and Maintenance

When used, ARBs should be initiated with the starting doses shown in Table 15. Many of the considerations with initiation of an ARB are similar to those with initiation of an ACE inhibitor, as discussed previously. Blood pressure (including postural blood pressure changes), renal function, and potassium should be reassessed within 1 to 2 weeks after initiation and followed closely after changes in dose. Patients with systolic blood pressure <80 mm Hg, low serum sodium, diabetes mellitus, and impaired renal function merit close surveillance during therapy with inhibitors of the renin angiotensin-aldosterone system. Titration is generally achieved by doubling doses. For stable patients, it is reasonable to add therapy with beta-blocking agents before full target doses of either ACE inhibitors or ARBs are reached.

7.3.2.3.3 ARBs: Risks of Treatment

The risks of ARBs are attributed to suppression of angiotensin stimulation. These risks of hypotension, renal dysfunction, and hyperkalemia are greater when combined with another inhibitor of this neurohormonal axis, such as ACE inhibitors or aldosterone antagonists.

See Online Data Supplement 19 for additional data on ARBs.

7.3.2.4 Beta Blockers: Recommendation

Class I

• 1. Use of 1 of the 3 beta blockers proven to reduce mortality (e.g., bisoprolol, carvedilol, and sustained-release metoprolol succinate) is recommended for all patients with current or prior symptoms of HFrEF, unless contraindicated, to reduce morbidity and mortality (346,416–419,448). (Level of Evidence: A)

Long-term treatment with beta blockers can lessen the symptoms of HF, improve the patient’s clinical status, and enhance the patient’s overall sense of well-being (462–469). In addition, like ACE inhibitors, beta blockers can reduce the risk of death and the combined risk of death or hospitalization (117,447,448,470,471). These benefits of beta blockers were seen in patients with or without CAD and in patients with or without diabetes mellitus, as well as in women and blacks. The favorable effects of beta blockers were also observed in patients already taking ACE inhibitors.

Three beta blockers have been shown to be effective in reducing the risk of death in patients with chronic HFrEF: bisoprolol and sustained-release metoprolol (succinate), which selectively block beta-1–receptors; and carvedilol, which blocks alpha-1–, beta-1–, and beta-2–receptors. Positive findings with these 3 agents, however, should not be considered a beta-blocker class effect. Bucindolol lacked uniform effectiveness across different populations, and short-acting metoprolol tartrate was less effective in HF clinical trials. Beta-1 selective blocker nebivolol demonstrated a modest reduction in the primary endpoint of all-cause mortality or cardiovascular hospitalization but did not affect mortality alone in an elderly population that included patients with HFpEF (472).

7.3.2.4.1 Beta Blockers: Selection of Patients

Beta blockers should be prescribed to all patients with stable HFrEF unless they have a contraindication to their use or are intolerant of these drugs. Because of its favorable effects on survival and disease progression, a clinical trial–proven beta blocker should be initiated as soon as HFrEF is diagnosed. Even when symptoms are mild or improve with other therapies, beta-blocker therapy is important and should not be delayed until symptoms return or disease progression is documented. Therefore, even if patients have little disability and experience seemingly minimal symptomatic benefit, they should still be treated with a beta blocker to reduce the risks of disease progression, clinical deterioration, and sudden death (117,448,469–471).

Patients need not take high doses of ACE inhibitors before initiation of beta-blocker therapy. In patients taking a low dose of an ACE inhibitor, the addition of a beta blocker produces a greater improvement in symptoms and reduction in the risk of death than does an increase in the dose of the ACE inhibitor, even to the target doses used in clinical trials (445,473). In patients with a current or recent history of fluid retention, beta blockers should not be prescribed without diuretics, because diuretics are needed to maintain sodium and fluid balance and prevent the exacerbation of fluid retention that can accompany the initiation of beta-blocker therapy (474,475). Beta blockers may be considered in patients who have reactive airway disease or asymptomatic bradycardia but should be used cautiously in patients with persistent symptoms of either condition.

7.3.2.4.2 Beta Blockers: Initiation and Maintenance

Treatment with a beta blocker should be initiated at very low doses (Table 15), followed by gradual increments in dose if lower doses have been well tolerated. Patients should be monitored closely for changes in vital signs and symptoms during this uptitration period. Planned increments in the dose of a beta blocker should be delayed until any adverse effects observed with lower doses have disappeared. When such a cautious approach was used, most patients (approximately 85%) enrolled in clinical trials who received beta blockers were able to tolerate short- and long-term treatment with these drugs and achieve the maximum planned trial dose (117,447,448,470). Data show that beta blockers can be safely started before discharge even in patients hospitalized for HF, provided they do not require intravenous inotropic therapy for HF (476). Clinicians should make every effort to achieve the target doses of the beta blockers shown to be effective in major clinical trials. Even if symptoms do not improve, long-term treatment should be maintained to reduce the risk of major clinical events. Abrupt withdrawal of treatment with a beta blocker can lead to clinical deterioration and should be avoided (477).

7.3.2.4.3 Beta Blockers: Risks of Treatment

Initiation of treatment with a beta blocker may produce 4 types of adverse reactions that require attention and management: fluid retention and worsening HF; fatigue; bradycardia or heart block; and hypotension. The occurrence of fluid retention or worsening HF is not generally a reason for the permanent withdrawal of treatment. Such patients generally respond favorably to intensification of conventional therapy, and once treated, they remain excellent candidates for long-term treatment with a beta blocker. The slowing of heart rate and cardiac conduction produced by beta blockers is generally asymptomatic and thus requires no treatment; however, if the bradycardia is accompanied by dizziness or lightheadedness or if second- or third-degree heart block occurs, clinicians should decrease the dose of the beta blocker. Clinicians may minimize the risk of hypotension by administering the beta blocker and ACE inhibitor at different times during the day. Hypotensive symptoms may also resolve after a decrease in the dose of diuretics in patients who are volume depleted. If hypotension is accompanied by other clinical evidence of hypoperfusion, beta-blocker therapy should be decreased or discontinued pending further patient evaluation. The symptom of fatigue is multifactorial and is perhaps the hardest symptom to address with confidence. Although fatigue may be related to beta blockers, other causes of fatigue should be considered, including sleep apnea, overdiuresis, or depression.

See Online Data Supplement 20 for additional data on beta blockers.

7.3.2.5 Aldosterone Receptor Antagonists: Recommendations

Class I

• 1. Aldosterone receptor antagonists (or mineralocorticoid receptor antagonists) are recommended in patients with NYHA class II–IV HF and who have LVEF of 35% or less, unless contraindicated, to reduce morbidity and mortality. Patients with NYHA class II HF should have a history of prior cardiovascular hospitalization or elevated plasma natriuretic peptide levels to be considered for aldosterone receptor antagonists. Creatinine should be 2.5 mg/dL or less in men or 2.0 mg/dL or less in women (or estimated glomerular filtration rate >30 mL/min/1.73 m²), and potassium should be less than 5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely followed thereafter to minimize risk of hyperkalemia and renal insufficiency (425,426,478). (Level of Evidence: A)

• 2. Aldosterone receptor antagonists are recommended to reduce morbidity and mortality following an acute MI in patients who have LVEF of 40% or less who develop symptoms of HF or who have a history of diabetes mellitus, unless contraindicated (446). (Level of Evidence: B)

Class III: Harm

• 1. Inappropriate use of aldosterone receptor antagonists is potentially harmful because of life-threatening hyperkalemia or renal insufficiency when serum creatinine is greater than 2.5 mg/dL in men or greater than 2.0 mg/dL in women (or estimated glomerular filtration rate <30 mL/min/1.73 m²), and/or potassium greater than 5.0 mEq/L (479,480). (Level of Evidence: B)

The landmark RALES trial (Randomized Aldactone Evaluation Study) (425) showed a 30% reduction in all-cause mortality as well as a reduced risk of SCD and HF hospitalizations with the use of spironolactone in patients with chronic HFrEF and LVEF <35%. Eplerenone has been shown to reduce all-cause deaths, cardiovascular deaths, or HF hospitalizations in a wider range of patients with HFrEF (426,446).

7.3.2.5.1 Aldosterone Receptor Antagonists: Selection of Patients

Clinicians should strongly consider the addition of the aldosterone receptor antagonists spironolactone or eplerenone for all patients with HFrEF who are already on ACE inhibitors (or ARBs) and beta blockers. Although the entry criteria for the trials of aldosterone receptor antagonists excluded patients with a creatinine >2.5 mg/dL, the majority of patients had much lower creatinine (95% of patients had creatinine ≤1.7 mg/dL) (425,426,446). In contrast, one third of patients in EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) had an estimated glomerular filtration rate of <60 mL/min/1.73 m² (426). Note also that the entry criteria for the EMPHASIS-HF trial were age of at least ≥55 years, NYHA class II symptoms, and an EF of no more than 30% (or, if >30% to 35%, a QRS duration of >130 ms on ECG). To minimize the risk of life-threatening hyperkalemia in euvolemic patients with HFrEF, patients should have initial serum creatinine <2.5 mg/dL (or an estimated glomerular filtration rate >30 mL/min/1.73 m²) without recent worsening and serum potassium <5.0 mEq/L without a history of severe hyperkalemia. Careful patient selection and risk assessment with availability of close monitoring is essential in initiating the use of aldosterone receptor antagonists.

7.3.2.5.2 Aldosterone Receptor Antagonists: Initiation and Maintenance

Spironolactone should be initiated at a dose of 12.5 to 25 mg daily, while eplerenone should be initiated at a dose of 25 mg/d, increasing to 50 mg daily. For those with concerns of hyperkalemia or marginal renal function (estimated glomerular filtration rate 30 to 49 mL/min/1.73 m²), an initial regimen of every-other-day dosing is advised (Table 16). After initiation of aldosterone receptor antagonists, potassium supplementation should be discontinued (or reduced and carefully monitored in those with a history of hypokalemia; Table 17), and patients should be counseled to avoid foods high in potassium and NSAIDs. Potassium levels and renal function should be rechecked within 2 to 3 days and again at 7 days after initiation of an aldosterone receptor antagonist. Subsequent monitoring should be dictated by the general clinical stability of renal function and fluid status but should occur at least monthly for the first 3 months and every 3 months thereafter. The addition or an increase in dosage of ACE inhibitors or ARBs should trigger a new cycle of monitoring.

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Table 16

Drug Dosing for Aldosterone Receptor Antagonists

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Table 17

Strategies to Minimize the Risk of Hyperkalemia in Patients Treated With Aldosterone Antagonists

There are limited data to support or refute that spironolactone and eplerenone are interchangeable. The perceived difference between eplerenone and spironolactone is the selectivity of aldosterone receptor antagonism and not the effectiveness of blocking mineralocorticoid activity. In RALES, there was increased incidence (10%) of gynecomastia or breast pain with use of spironolactone (a nonselective antagonist). The incidence of these adverse events was <1% in EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) and EMPHASIS-HF without any difference in adverse events between the eplerenone and placebo (426,446).

7.3.2.5.3 Aldosterone Receptor Antagonists: Risks of Treatment

The major risk associated with use of aldosterone receptor antagonists is hyperkalemia due to inhibition of potassium excretion, ranging from 2% to 5% in large clinical trials (425,426,446) to 24% to 36% in population-based registries (479,480). Routine triple combination of an ACE inhibitor, ARB, and aldosterone receptor antagonist should be avoided.

The development of potassium levels >5.5 mEq/L (approximately 12% in EMPHASIS-HF [426]) should generally trigger discontinuation or dose reduction of the aldosterone receptor antagonist unless other causes are identified. The development of worsening renal function should lead to careful evaluation of the entire medical regimen and consideration for stopping the aldosterone receptor antagonist. Patients should be instructed specifically to stop the aldosterone receptor antagonist during an episode of diarrhea or dehydration or while loop diuretic therapy is interrupted.

7.3.2.6 Hydralazine and Isosorbide Dinitrate: Recommendations

Class I

• 1. The combination of hydralazine and isosorbide dinitrate is recommended to reduce morbidity and mortality for patients self-described as African Americans with NYHA class III–IV HFrEF receiving optimal therapy with ACE inhibitors and beta blockers, unless contraindicated (423,424). (Level of Evidence: A)

Class IIa

• 1. A combination of hydralazine and isosorbide dinitrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated (449). (Level of Evidence: B)

In a large-scale trial that compared the vasodilator combination with placebo, the use of hydralazine and isosorbide dinitrate reduced mortality but not hospitalizations in patients with HF treated with digoxin and diuretics but not an ACE inhibitor or beta blocker (449). However, in 2 other trials that compared the vasodilator combination with an ACE inhibitor, the ACE inhibitor produced more favorable effects on survival (412,482). A post hoc retrospective analysis of these vasodilator trials demonstrated particular efficacy of isosorbide dinitrate and hydralazine in the African American cohort (423). In a subsequent trial, which was limited to patients self-described as African American, the addition of a fixed-dose combination of hydralazine and isosorbide dinitrate to standard therapy with an ACE inhibitor or ARB, a beta blocker, and an aldosterone antagonist offered significant benefit (424).

7.3.2.6.1 Hydralazine and Isosorbide Dinitrate: Selection of Patients

The combination of hydralazine and isosorbide dinitrate is recommended for African Americans with HFrEF who remain symptomatic despite concomitant use of ACE inhibitors, beta blockers, and aldosterone antagonists. Whether this benefit is evident in non–African Americans with HFrEF remains to be investigated. The combination of hydralazine and isosorbide dinitrate should not be used for the treatment of HFrEF in patients who have no prior use of standard neurohumoral antagonist therapy and should not be substituted for ACE inhibitor or ARB therapy in patients who are tolerating therapy without difficulty. Despite the lack of data with the vasodilator combination in patients who are intolerant of ACE inhibitors or ARBs, the combined use of hydralazine and isosorbide dinitrate may be considered as a therapeutic option in such patients.

7.3.2.6.2 Hydralazine and Isosorbide Dinitrate: Initiation and Maintenance

If the fixed-dose combination is available, the initial dose should be 1 tablet containing 37.5 mg of hydralazine hydrochloride and 20 mg of isosorbide dinitrate 3 times daily. The dose can be increased to 2 tablets 3 times daily for a total daily dose of 225 mg of hydralazine hydrochloride and 120 mg of isosorbide dinitrate. When the 2 drugs are used separately, both pills should be administered at least 3 times daily. Initial low doses of the drugs given separately may be progressively increased to a goal similar to that achieved in the fixed-dose combination trial (424).

7.3.2.6.3 Hydralazine and Isosorbide Dinitrate: Risks of Treatment

Adherence to this combination has generally been poor because of the large number of tablets required, frequency of administration, and the high incidence of adverse reactions (412,449). Frequent adverse effects include headache, dizziness, and gastrointestinal complaints. Nevertheless, the benefit of these drugs can be substantial and warrant a slower titration of the drugs to enhance tolerance of the therapy.

See Table 18 for a summary of the treatment benefit of GDMT in HFrEF.

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Table 18

Medical Therapy for Stage C HFrEF: Magnitude of Benefit Demonstrated in RCTs

7.3.2.7 Digoxin: Recommendation

Class IIa

• 1. Digoxin can be beneficial in patients with HFrEF, unless contraindicated, to decrease hospitalizations for HF (484–491). (Level of Evidence: B)

Several placebo-controlled trials have shown that treatment with digoxin for 1 to 3 months can improve symptoms, HRQOL, and exercise tolerance in patients with mild to moderate HF (485–491). These benefits have been seen regardless of the underlying rhythm (normal sinus rhythm or AF), cause of HF (ischemic or nonischemic cardiomyopathy), or concomitant therapy (with or without ACE inhibitors). In a long-term trial that primarily enrolled patients with NYHA class II or III HF, treatment with digoxin for 2 to 5 years had no effect on mortality but modestly reduced the combined risk of death and hospitalization (484).

7.3.2.7.1 Digoxin: Selection of Patients

Clinicians may consider adding digoxin in patients with persistent symptoms of HFrEF during GDMT. Digoxin may also be added to the initial regimen in patients with severe symptoms who have not yet responded symptomatically during GDMT.

Alternatively, treatment with digoxin may be delayed until the patient’s response to GDMT has been defined and may be used only in patients who remain symptomatic despite therapy with the neurohormonal antagonists. If a patient is taking digoxin but not an ACE inhibitor or a beta blocker, treatment with digoxin should not be withdrawn, but appropriate therapy with the neurohormonal antagonists should be instituted. Digoxin is prescribed occasionally in patients with HF and AF, but beta blockers are usually more effective when added to digoxin in controlling the ventricular response, particularly during exercise (492–495).

Patients should not be given digoxin if they have significant sinus or atrioventricular block unless the block has been addressed with a permanent pacemaker. The drug should be used cautiously in patients taking other drugs that can depress sinus or atrioventricular nodal function or affect digoxin levels (e.g., amiodarone or a beta blocker), even though such patients usually tolerate digoxin without difficulty.

7.3.2.7.2 Digoxin: Initiation and Maintenance

Therapy with digoxin is commonly initiated and maintained at a dose of 0.125 to 0.25 mg daily. Low doses (0.125 mg daily or every other day) should be used initially if the patient is >70 years of age, has impaired renal function, or has a low lean body mass (496). Higher doses (e.g., digoxin 0.375 to 0.50 mg daily) are rarely used or needed in the management of patients with HF. There is no reason to use loading doses of digoxin to initiate therapy in patients with HF.

Doses of digoxin that achieve a plasma concentration of drug in the range of 0.5 to 0.9 ng/mL are suggested, given the limited evidence currently available. There has been no prospective, randomized evaluation of the relative efficacy or safety of different plasma concentrations of digoxin. Retrospective analysis of 2 studies of digoxin withdrawal found that prevention of worsening HF by digoxin at lower concentrations in plasma (0.5 to 0.9 ng/mL) was as great as that achieved at higher concentrations (497,498).

7.3.2.7.3 Digoxin: Risks of Treatment

When administered with attention to dose and factors that alter its metabolism, digoxin is well tolerated by most patients with HF (499). The principal adverse reactions occur primarily when digoxin is administered in large doses, especially in the elderly, but large doses are not necessary for clinical benefits (500–502). The major adverse effects include cardiac arrhythmias (e.g., ectopic and re-entrant cardiac rhythms and heart block), gastrointestinal symptoms (e.g., anorexia, nausea, and vomiting), and neurological complaints (e.g., visual disturbances, disorientation, and confusion). Overt digoxin toxicity is commonly associated with serum digoxin levels >2 ng/mL.

However, toxicity may also occur with lower digoxin levels, especially if hypokalemia, hypomagnesemia, or hypothyroidism coexists (503,504). The concomitant use of clarithromycin, dronedarone, erythromycin, amiodarone, itraconazole, cyclosporine, propafenone, verapamil, or quinidine can increase serum digoxin concentrations and may increase the likelihood of digoxin toxicity (505–507). The dose of digoxin should be reduced if treatment with these drugs is initiated. In addition, a low lean body mass and impaired renal function can also elevate serum digoxin levels, which may explain the increased risk of digoxin toxicity in elderly patients.

7.3.2.8 Other Drug Treatment

7.3.2.8.1 Anticoagulation: Recommendations

Class I

• 1. Patients with chronic HF with permanent/persistent/paroxysmal AF and an additional risk factor for cardioembolic stroke (history of hypertension, diabetes mellitus, previous stroke or transient ischemic attack, or ≥75 years of age) should receive chronic anticoagulant therapy* (508–514). (Level of Evidence: A)

• 2. The selection of an anticoagulant agent (warfarin, dabigatran, apixaban, or rivaroxaban) for permanent/persistent/paroxysmal AF should be individualized on the basis of risk factors, cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including time in the international normalized ratio therapeutic range if the patient has been taking warfarin. (Level of Evidence: C)

Class IIa

• 1. Chronic anticoagulation is reasonable for patients with chronic HF who have permanent/persistent/paroxysmal AF but are without an additional risk factor for cardioembolic stroke∗ (509–511,515–517). (Level of Evidence: B)

Class III: No Benefit

• 1. Anticoagulation is not recommended in patients with chronic HFrEF without AF, a prior thromboembolic event, or a cardioembolic source (518–520). (Level of Evidence: B)

Patients with chronic HFrEF are at an increased risk of thromboembolic events due to stasis of blood in dilated hypokinetic cardiac chambers and in peripheral blood vessels (521,522) and perhaps due to increased activity of procoagulant factors (523). However, in large-scale studies, the risk of thromboembolism in clinically stable patients has been low (1% to 3% per year), even in those with a very depressed EF and echocardiographic evidence of intracardiac thrombi (524–528). These rates are sufficiently low to limit the detectable benefit of anticoagulation in these patients.

In several retrospective analyses, the risk of thromboembolic events was not lower in patients with HF taking warfarin than in patients not treated with antithrombotic drugs (524,526,527). The use of warfarin was associated with a reduction in major cardiovascular events and death in patients with HF in some studies but not in others (518,529,530). An RCT that compared the outcome of patients with HFrEF assigned to aspirin, warfarin, or clopidogrel was completed (519), but no therapy appeared to be superior. Another trial compared aspirin with warfarin in patients with reduced LVEF, sinus rhythm, and no cardioembolic source and demonstrated no difference in either the primary outcome of death, stroke, or intracerebral hemorrhage (520). There was also no difference in the combined outcome of death, ischemic stroke, intracerebral hemorrhage, MI, or HF hospitalization. There was a significant increase in major bleeding with warfarin. Given that there is no overall benefit of warfarin and an increased risk of bleeding, there is no compelling evidence to use warfarin or aspirin in patients with HFrEF in the absence of a specific indication.

The efficacy of long-term warfarin for the prevention of stroke in patients with AF is well established. However, the ACCF/AHA guidelines for AF (6) recommend use of the CHADS₂ [Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, previous Stroke/transient ischemic attack (doubled risk weight)] score to assess patient risk for adverse outcomes before initiating anticoagulation therapy. More recently, a revised score, CHADS2-VASc, has been suggested as more applicable to a wider range of patients (531), but this revised score has not yet been fully studied in patients with HF. Regardless of whether patients receive rhythm or rate control, anticoagulation is recommended for patients with HF and AF for stroke prevention in the presence of at least 1 additional risk factor. For patients with HF and AF in the absence of another cardioembolic risk factor, anticoagulation is reasonable.

Trials of newer oral anticoagulants have compared efficacy and safety with warfarin therapy rather than placebo. Several new oral anticoagulants are now available, including the factor Xa inhibitors apixaban and rivaroxaban and the direct thrombin inhibitor dabigatran (508,512–514). These drugs have few food and drug interactions compared with warfarin and no need for routine coagulation monitoring or dose adjustment. The fixed dosing together with fewer interactions may simplify patient management, particularly with the polypharmacy commonly seen in HF. These drugs have a potential for an improved benefit–risk profile compared with warfarin, which may increase their use in practice, especially in those at increased bleeding risk. However, important adverse effects have been noted with these new anticoagulants, including gastrointestinal distress, which may limit compliance. At present, there is no commercially available agent to reverse the effect of these newer drugs. Trials comparing new anticoagulants with warfarin have enrolled >10,000 patients with HF. As more detailed evaluations of the comparative benefits and risks of these newer agents in patients with HF are still pending, the writing committee considered their use in patients with HF and nonvalvular AF as an alternative to warfarin to be reasonable.

The benefit afforded by low-dose aspirin in patients with systolic HF but no previous MI or known CAD (or specifically in patients proven free of CAD) remains unknown. A Cochrane review failed to find sufficient evidence to support its use (532). Retrospective and observational studies again had conflicting results and used very different criteria to identify patients as nonischemic, with some demonstrating protection from aspirin overall (532) or only in patients with more severe depression of systolic function (518), whereas others found no benefit from aspirin (530). The high incidence of diabetes mellitus and hypertension in most HF studies, combined with a failure to use objective methods to exclude CAD in enrolled patients, may leave this question unanswered. Currently, data are insufficient to recommend aspirin for empiric primary prevention in HF patients known to be free of atherosclerotic disease and without additional risk factors.

See Online Data Supplement 21 for additional data on anticoagulants.

7.3.2.8.2 Statins: Recommendation

Class III: No Benefit

• 1. Statins are not beneficial as adjunctive therapy when prescribed solely for the diagnosis of HF in the absence of other indications for their use (533–538). (Level of Evidence: A)

Statin therapy has been broadly implicated in prevention of adverse cardiovascular events, including new-onset HF. Originally designed to lower cholesterol in patients with cardiovascular disease, statins are increasingly recognized for their favorable effects on inflammation, oxidative stress, and vascular performance. Several observational and post hoc analyses from large clinical trials have implied that statin therapy may provide clinical benefit to patients with HF (533–536). However, 2 large RCTs have demonstrated that rosuvastatin has neutral effects on long-term outcomes in patients with chronic HFrEF when added to standard GDMT (537,538). At present, statin therapy should not be prescribed primarily for the treatment of HF to improve clinical outcomes.

See Online Data Supplement 22 for additional data on statin therapy.

7.3.2.8.3 Omega-3 Fatty Acids: Recommendation

Class IIa

• 1. Omega-3 polyunsaturated fatty acid (PUFA) supplementation is reasonable to use as adjunctive therapy in patients with NYHA class II–IV symptoms and HFrEF or HFpEF, unless contraindicated, to reduce mortality and cardiovascular hospitalizations (539,540). (Level of Evidence: B)

Supplementation with omega-3 PUFA has been evaluated as an adjunctive therapy for cardiovascular disease and HF (541). Trials in primary and secondary prevention of coronary heart disease showed that omega-3 PUFA supplementation results in a 10% to 20% risk reduction in fatal and nonfatal cardiovascular events. The GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico) Prevenzione trial demonstrated a 21% reduction in death among post-MI patients taking 1 g of omega-3 PUFA (850 mg to 882 mg of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] as ethyl esters in the ratio of 1:1.2) (542). Post hoc subgroup analysis revealed that this reduction in mortality and SCD was concentrated in the approximately 2000 patients with reduced LVEF (539). The GISSI-HF investigators randomized 6,975 patients in NYHA class II–IV chronic HF to 1 g daily of omega-3 PUFA (850 mg to 882 mg EPA/DHA) or matching placebo. Death from any cause was reduced from 29% with placebo to 27% in those treated with omega-3 PUFA (540). The outcome of death or admission to hospital for a cardiovascular event was also significantly reduced. In reported studies, this therapy has been safe and very well tolerated (540–543). Further investigations are needed to better define optimal dosing and formulation of omega-3 PUFA supplements. The use of omega-3 PUFA supplementation is reasonable as adjunctive therapy in patients with chronic HF.

See Online Data Supplement 23 for additional data on omega-3 fatty acids.

7.3.2.9 Drugs of Unproven Value or That May Worsen HF: Recommendations

Class III: No Benefit

• 1. Nutritional supplements as treatment for HF are not recommended in patients with current or prior symptoms of HFrEF (544,545). (Level of Evidence: B)

• 2. Hormonal therapies other than to correct deficiencies are not recommended for patients with current or prior symptoms of HFrEF. (Level of Evidence: C)

Class III: Harm

• 1. Drugs known to adversely affect the clinical status of patients with current or prior symptoms of HFrEF are potentially harmful and should be avoided or withdrawn whenever possible (e.g., most antiarrhythmic drugs, most calcium channel–blocking drugs [except amlodipine], NSAIDs, or thiazolidinediones) (546–557). (Level of Evidence: B)

• 2. Long-term use of infused positive inotropic drugs is potentially harmful for patients with HFrEF, except as palliation for patients with end-stage disease who cannot be stabilized with standard medical treatment (see recommendations for stage D). (Level of Evidence: C)

7.3.2.9.1 Nutritional Supplements and Hormonal Therapies

Patients with HF, particularly those treated with diuretics, may become deficient in vitamins and micronutrients. Several nutritional supplements (e.g., coenzyme Q10, carnitine, taurine, and antioxidants) and hormonal therapies (e.g., growth hormone or thyroid hormone) have been proposed for the treatment of HF (558–563). Testosterone has also been evaluated for its beneficial effect in HF with modest albeit preliminary effects (564). Aside from replenishment of documented deficiencies, published data have failed to demonstrate benefit for routine vitamin, nutritional, or hormonal supplementation (565). In most data or other literature regarding nutraceuticals, there are issues, including outcomes analyses, adverse effects, and drug-nutraceutical interactions, that remain unresolved.

No clinical trials have demonstrated improved survival rates with use of nutritional or hormonal therapy, with the exception of omega-3 fatty acid supplementation as previously noted. Some studies have suggested a possible effect for coenzyme Q10 in reduced hospitalization rates, dyspnea, and edema in patients with HF, but these benefits have not been seen uniformly (566–569). Because of possible adverse effects and drug interactions of nutritional supplements and their widespread use, clinicians caring for patients with HF should routinely inquire about their use. Until more data are available, nutritional supplements or hormonal therapies are not recommended for the treatment of HF.

7.3.2.9.2 Antiarrhythmic Agents

With atrial and ventricular arrhythmias contributing to the morbidity and mortality of HF, various classes of antiarrhythmic agents have been repeatedly studied in large RCTs. Instead of conferring survival benefit, however, nearly all antiarrhythmic agents increase mortality in the HF population (548–550). Most antiarrhythmics have some negative inotropic effect and some, particularly the class I and class III antiarrhythmic drugs, have proarrhythmic effects. Hence, class I sodium channel antagonists and the class III potassium channel blockers d-sotalol and dronedarone should be avoided in patients with HF. Amiodarone and dofetilide are the only antiarrhythmic agents to have neutral effects on mortality in clinical trials of patients with HF and thus are the preferred drugs for treating arrhythmias in this patient group (570–573).

See Online Data Supplement 24 for additional data on antiarrhythmic agents.

7.3.2.9.3 Calcium Channel Blockers: Recommendation

Class III: No Benefit

• 1. Calcium channel–blocking drugs are not recommended as routine treatment for patients with HFrEF (551,574,575). (Level of Evidence: A)

By reducing peripheral vasoconstriction and LV afterload, calcium channel blockers were thought to have a potential role in the management of chronic HF. However, first-generation dihydropyridine and nondihydropyridine calcium channel blockers also have myocardial depressant activity. Several clinical trials have demonstrated either no clinical benefit or even worse outcomes in patients with HF treated with these drugs (546,547,551–553). Despite their greater selectivity for calcium channels in vascular smooth muscle cells, second-generation calcium channel blockers, dihydropyridine derivatives such as amlodipine and felodipine, have failed to demonstrate any functional or survival benefit in patients with HF (575–579). Amlodipine, however, may be considered in the management of hypertension or ischemic heart disease in patients with HF because it is generally well tolerated and had neutral effects on morbidity and mortality in large RCTs. In general, calcium channel blockers should be avoided in patients with HFrEF.

See Online Data Supplement 25 for additional data on calcium channel blockers.

7.3.2.9.4 Nonsteroidal Anti-Inflammatory Drugs

NSAIDs inhibit the synthesis of renal prostaglandins, which mediate vasodilation in the kidneys and directly inhibit sodium resorption in the thick ascending loop of Henle and collecting tubule. Hence, NSAIDs can cause sodium and water retention and blunt the effects of diuretics. Several observational cohort studies have revealed increased morbidity and mortality in patients with HF using either nonselective or selective NSAIDs (554–556,580–582).

See Online Data Supplement 26 for additional data on NSAIDs.

7.3.2.9.5 Thiazolidinediones

Thiazolidinediones increase insulin sensitivity by activating nuclear peroxisome proliferator-activated receptor gamma. Expressed in virtually all tissues, peroxisome proliferator-activated receptor gamma also regulates sodium reabsorption in the collecting ducts of the kidney. In clinical trials, thiazolidinediones have been associated with increased incidence of HF events, even in those without any prior history of clinical HF (557,583–588).

See Table 19 for a summary of recommendations from this section and Table 20 for strategies for achieving optimal GDMT; see Online Data Supplement 27 for additional data on thiazolidinediones.

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Table 19

Recommendations for Pharmacological Therapy for Management of Stage C HFrEF

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Table 20

Strategies for Achieving Optimal GDMT

7.3.4 Device Therapy for Stage C HFrEF: Recommendations

See Table 22 for a summary of recommendations from this section.

Class I

• 1. ICD therapy is recommended for primary prevention of SCD to reduce total mortality in selected patients with nonischemic DCM or ischemic heart disease at least 40 days post-MI with LVEF of 35% or less and NYHA class II or III symptoms on chronic GDMT, who have reasonable expectation of meaningful survival for more than 1 year† (355,593). (Level of Evidence: A)

• 2. CRT is indicated for patients who have LVEF of 35% or less, sinus rhythm, left bundle-branch block (LBBB) with a QRS duration of 150 ms or greater, and NYHA class II, III, or ambulatory IV symptoms on GDMT. (Level of Evidence: A for NYHA class III/IV (38,78,116,594); Level of Evidence: B for NYHA class II (595,596)).

• 3. ICD therapy is recommended for primary prevention of SCD to reduce total mortality in selected patients at least 40 days post-MI with LVEF of 30% or less, and NYHA class I symptoms while receiving GDMT, who have reasonable expectation of meaningful survival for more than 1 year† (362,597,598). (Level of Evidence: B)

Class IIa

• 1. CRT can be useful for patients who have LVEF of 35% or less, sinus rhythm, a non-LBBB pattern with a QRS duration of 150 ms or greater, and NYHA class III/ambulatory class IV symptoms on GDMT (78,116,594,596). (Level of Evidence: A)

• 2. CRT can be useful for patients who have LVEF of 35% or less, sinus rhythm, LBBB with a QRS duration of 120 to 149 ms, and NYHA class II, III, or ambulatory IV symptoms on GDMT (78,116,594–596,599). (Level of Evidence: B)

• 3. CRT can be useful in patients with AF and LVEF of 35% or less on GDMT if a) the patient requires ventricular pacing or otherwise meets CRT criteria and b) atrioventricular nodal ablation or pharmacological rate control will allow near 100% ventricular pacing with CRT (600–605). (Level of Evidence: B)

• 4. CRT can be useful for patients on GDMT who have LVEF of 35% or less and are undergoing placement of a new or replacement device implantation with anticipated requirement for significant (>40%) ventricular pacing (155,602,606,607). (Level of Evidence: C)

Class IIb

• 1. The usefulness of implantation of an ICD is of uncertain benefit to prolong meaningful survival in patients with a high risk of nonsudden death as predicted by frequent hospitalizations, advanced frailty, or comorbidities such as systemic malignancy or severe renal dysfunction† (608–611). (Level of Evidence: B)

• 2. CRT may be considered for patients who have LVEF of 35% or less, sinus rhythm, a non-LBBB pattern with QRS duration of 120 to 149 ms, and NYHA class III/ambulatory class IV on GDMT (596,612). (Level of Evidence: B)

• 3. CRT may be considered for patients who have LVEF of 35% or less, sinus rhythm, a non-LBBB pattern with a QRS duration of 150 ms or greater, and NYHA class II symptoms on GDMT (595,596). (Level of Evidence: B)

• 4. CRT may be considered for patients who have LVEF of 30% or less, ischemic etiology of HF, sinus rhythm, LBBB with a QRS duration of 150 ms or greater, and NYHA class I symptoms on GDMT (595,596). (Level of Evidence: C)

Class III: No Benefit

• 1. CRT is not recommended for patients with NYHA class I or II symptoms and non-LBBB pattern with QRS duration less than 150 ms (595,596,612). (Level of Evidence: B)

• 2. CRT is not indicated for patients whose comorbidities and/or frailty limit survival with good functional capacity to less than 1 year (38). (Level of Evidence: C)

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Table 22

Recommendations for Device Therapy for Management of Stage C HF

See Figure 2, indications for CRT therapy algorithm.

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Figure 2

Indications for CRT therapy algorithm. CRT indicates cardiac resynchronization therapy; CRT-D, cardiac resynchronization therapy-defibrillator; GDMT, guideline-directed medical therapy; HF, heart failure; ICD, implantable cardioverter-defibrillator; LBBB, left bundle-branch block; LVEF, left ventricular ejection fraction; MI, myocardial infarction; and NYHA, New York Heart Association.

7.3.4.1 Implantable Cardioverter-Defibrillator

Patients with reduced LVEF are at increased risk for ventricular tachyarrhythmias leading to SCD. Sudden death in HFrEF has been substantially decreased by neurohormonal antagonists that alter disease progression and also protect against arrhythmias. Nonetheless, patients with systolic dysfunction remain at increased risk for SCD due to ventricular tachyarrhythmias. Patients who have had sustained ventricular tachycardia, ventricular fibrillation, unexplained syncope, or cardiac arrest are at highest risk for recurrence. Indications for ICD therapy as secondary prevention of SCD in these patients are also discussed in the ACCF/AHA/HRS device-based therapy guideline (4).

The use of ICDs for primary prevention of SCD in patients with HFrEF without prior history of arrhythmias or syncope has been evaluated in multiple RCTs. ICD therapy for primary prevention was demonstrated to reduce all-cause mortality. For patients with LVEF ≤30% after remote MI, use of ICD therapy led to a 31% decrease in mortality over 20 months, for an absolute decrease of 5.6% (362). For patients with mild to moderate symptoms of HF with LVEF ≤35% due either to ischemic or nonischemic etiology, there was a 23% decrease in mortality over a 5-year period, for an absolute decrease of 7.2% (593). For both these trials, the survival benefit appeared after the first year. Other smaller trials were consistent with this degree of benefit, except for patients within the first 40 days after acute MI, in whom SCD was decreased but there was an increase in other events such that there was no net benefit for survival (598,614). Both SCD and total mortality are highest in patients with HFrEF with class IV symptoms, in whom ICDs are not expected to prolong meaningful survival and are not indicated except in those for whom heart transplantation or MCS is anticipated.

The use of ICDs for primary prevention in patients with HFrEF should be considered only in the setting of optimal GDMT and with a minimum of 3 to 6 months of appropriate medical therapy. A repeat assessment of ventricular function is appropriate to assess any recovery of ventricular function on GDMT that would be above the threshold where an ICD is indicated. This therapy will often improve ventricular function to a range for which the risk of sudden death is too low to warrant placement of an ICD. In addition, the trials of ICDs for primary prevention of SCD studied patients who were already on GDMT.

ICDs are highly effective in preventing death from ventricular arrhythmias, but frequent shocks can decrease HRQOL and lead to posttraumatic stress syndrome (615). Therapy with antiarrhythmic drugs and catheter ablation for ventricular tachycardia can decrease the number of ICD shocks given and can sometimes improve ventricular function in cases of very frequent ventricular tachyarrhythmias. Refined device programming can optimize pacing therapies to avert the need for shocks, minimize inappropriate shocks, and avoid aggravation of HF by frequent ventricular pacing. Although there have been occasional recalls of device generators, these are exceedingly rare in comparison to complications related to intracardiac device leads, such as fracture and infection.

ICDs are indicated only in patients with a reasonable expectation of survival with good functional status beyond a year, but the range of uncertainty remains wide. The complex decision about the relative risks and benefits of ICDs for primary prevention of SCD must be individualized for each patient. Unlike other therapies that can prolong life with HF, the ICD does not modify the disease except in conjunction with CRT. Patients with multiple comorbidities have a higher rate of implant complications and higher competing risks of death from noncardiac causes (616). Older patients, who are at a higher risk of nonsudden death, are often underrepresented in the pivotal trials where the average patient is <65 years of age (617). The major trials for secondary prevention of SCD showed no benefit in patients >75 years of age (618), and a meta-analysis of primary prevention of SCD also suggested lesser effectiveness of ICDs (619). Populations of patients with multiple HF hospitalizations, particularly in the setting of chronic kidney disease, have a median survival rate of <2 years, during which the benefit of the ICD may not be realized (608). There is widespread recognition of the need for further research to identify patients most and least likely to benefit from ICDs for primary prevention of SCD in HF. Similar considerations apply to the decision to replace the device generator.

Consideration of ICD implantation is highly appropriate for shared decision making (30). The risks and benefits carry different relative values depending on patient goals and preferences. Discussion should include the potential for SCD and nonsudden death from HF or noncardiac conditions. Information should be provided in a format that patients can understand about the estimated efficacy, safety, and potential complications of an ICD and the ease with which defibrillation can be inactivated if no longer desired (620). As the prevalence of implantable devices increases, it is essential that clearly defined processes be in place to support patients and families when decisions about deactivation arise (621).

7.3.4.2 Cardiac Resynchronization Therapy

In approximately one third of patients, HF progression is accompanied by substantial prolongation of the QRS interval, which is associated with worse outcome (622). Multisite ventricular pacing (termed CRT or biventricular pacing) can improve ventricular contractile function, diminish secondary mitral regurgitation, reverse ventricular remodeling, and sustain improvement in LVEF. Increased blood pressure with CRT can allow increased titration of neurohormonal antagonist medications that may further contribute to improvement. Benefits were proven initially in trials of patients with NYHA class III or ambulatory class IV HF symptoms and QRS duration of ≥120 to 130 ms. These results have included a decrease of approximately 30% in rehospitalization and reductions in all-cause mortality in the range of 24% to 36%. Improvement in survival is evident as early as the first 3 months of therapy. Functional improvements have been demonstrated on average as a 1 to 2 mL/kg/min increase in peak oxygen consumption, 50- to 70-meter increase in 6-minute walk distance, and a reduction of 10 points or more in the 0- to 105-point scale of the Minnesota Living With Heart Failure Questionnaire, all considered clinically significant. These results include patients with a wide range of QRS duration and, in most cases, sinus rhythm (78,116,594,623).

Although it is still not possible to predict with confidence which patients will improve with CRT, further experiences have provided some clarification. Benefit appears confined largely to patients with a QRS duration of at least 150 ms and LBBB pattern (624–628). The weight of the evidence has been accumulated from patients with sinus rhythm, with meta-analyses indicating substantially less clinical benefit in patients with permanent AF (604,605). Because effective CRT requires a high rate of ventricular pacing (629), the benefit for patients with AF is most evident in patients who have undergone atrioventricular nodal ablation, which ensures obligate ventricular pacing (601–603).

In general, most data derive from patients with class III symptoms. Patients labeled as having class IV symptoms account for a small minority of patients enrolled. Furthermore, these patients, characterized as “ambulatory” NYHA class IV, are not refractory due to fluid retention, frequently hospitalized for HF, or dependent on continuous intravenous inotropic therapy. CRT should not be considered as “rescue” therapy for stage D HF. In addition, patients with significant noncardiac limitations are unlikely to derive major benefit from CRT.

Since publication of the 2009 HF guideline (38), new evidence supports extension of CRT to patients with milder symptoms. LV remodeling was consistently reversed or halted, with benefit also in reduction of HF hospitalizations (595,596,599). In this population with low 1-year mortality, reduction of HF hospitalization dominated the composite primary endpoints, but a mortality benefit was subsequently observed in a 2-year extended follow-up study (630) and in a meta-analysis of 5 trials of CRT in mild HF that included 4213 patients with class II symptoms (631). Overall benefits in class II HF were noted only in patients with QRS ≥150 ms and LBBB, with an adverse impact with shorter QRS duration or non-LBBB.

The entry criterion for LVEF in CRT trials has ranged from ≤30% to ≤40%. The trials with class III–IV symptoms included patients with LVEF ≤35% (78,116,594). The 2 individual trials showing improvement in mortality with class II HF included patients with LVEF ≤30% (632,633). Trials demonstrating significant improvement in LV size and EF have included patients with LVEF ≤35% (115) and LVEF ≤40% (599), which also showed reduction in the secondary endpoint of time to hospitalization and a reduction in the composite of clinical HF events comparable to that of all of the CRT trials (624). The congruence of evidence from the totality of CRT trials with regard to remodeling and HF events supports a common threshold of 35% for benefit from CRT in patients with class II, III, and IV HF symptoms. For patients with class II HF, all but 1 of the trials tested CRT in combination with an ICD, whereas there is evidence for benefit with both CRT-defibrillator and CRT alone in patients with class III–IV symptoms (78,116).

Although the weight of evidence is substantial for patients with class II symptoms, these CRT trials have included only 372 patients with class I symptoms, most with concomitant ICD for the postinfarction indication (595,599). Considering the risk–benefit ratio for class I, more concern is raised by the early adverse events, which in 1 trial occurred in 13% of patients with CRT-ICD compared with 6.7% in patients with ICD only (596). On the basis of limited data from MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy), CRT-ICD may be considered for patients with class I symptoms >40 days after MI, LVEF ≤30%, sinus rhythm, LBBB, and QRS ≥150 ms (595).

These indications for CRT all include expectation for ongoing GDMT and diuretic therapy as needed for fluid retention. In addition, regular monitoring is required after device implantation because adjustment of HF therapies and reprogramming of device intervals may be required. The trials establishing the benefit of these interventions were conducted in centers offering expertise in both implantation and follow-up. Recommendations for CRT are made with the expectation that they will be performed in centers with expertise and outcome comparable to that of the trials that provide the bases of evidence. The benefit–risk ratio for this intervention would be anticipated to be diminished for patients who do not have access to these specialized care settings or who are nonadherent.

See Online Data Supplements 28 and 29 for additional data on device therapy and CRT.

7.4 Stage D

7.4.6 Cardiac Transplantation: Recommendation

Class I

• 1. Evaluation for cardiac transplantation is indicated for carefully selected patients with stage D HF despite GDMT, device, and surgical management (680). (Level of Evidence: C)

Cardiac transplantation is considered the gold standard for the treatment of refractory end-stage HF. Since the first successful cardiac transplantation in 1967, advances in immunosuppressive therapy have vastly improved the long-term survival of transplant recipients with a 1-, 3-, and 5-year posttransplant survival rate of 87.8%, 78.5%, and 71.7% in adults, respectively (681). Similarly, cardiac transplantation has been shown to improve functional status and HRQOL (682–688). The greatest survival benefit is seen in those patients who are at highest risk of death from advanced HF (689). Cardiopulmonary exercise testing helps refine candidate selection (690–696). Data suggest acceptable posttransplant outcomes in patients with reversible pulmonary hypertension (697), hypertrophic cardiomyopathy (698), peripartum cardiomyopathy (699), restrictive cardiomyopathy (700,701), and muscular dystrophy (702). Selected patients with stage D HF and poor prognosis should be referred to a cardiac transplantation center for evaluation and transplant consideration. Determination of HF prognosis is addressed in Sections 6.1.2 and 7.4.2. The listing criteria and evaluation and management of patients undergoing cardiac transplantation are described in detail by the International Society for Heart and Lung Transplantation (680).

See Table 27 for a summary of recommendations from this section, Figure 3 for the stages of HF development; and Online Data Supplement 36 for additional data on transplantation.

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Figure 3

Stages in the development of HF and recommended therapy by stage. ACEI indicates angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin-receptor blocker; CAD, coronary artery disease; CRT, cardiac resynchronization therapy; DM, diabetes mellitus; EF, ejection fraction; GDMT, guideline-directed medical therapy; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HRQOL, health-related quality of life; HTN, hypertension; ICD, implantable cardioverter-defibrillator; LV, left ventricular; LVH, left ventricular hypertrophy; MCS, mechanical circulatory support; and MI, myocardial infarction.

Adapted from Hunt et al. (38).

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Table 27

Recommendations for Inotropic Support, MCS, and Cardiac Transplantation

8.1 Classification of Acute Decompensated HF

Hospitalization for HF is a growing and major public health issue (703). Presently, HF is the leading cause of hospitalization among patients >65 years of age (51); the largest percentage of expenditures related to HF are directly attributable to hospital costs. Moreover, in addition to costs, hospitalization for acutely decompensated HF represents a sentinel prognostic event in the course of many patients with HF, with a high risk for recurrent hospitalization (e.g., 50% at 6 months) and a 1-year mortality rate of approximately 30% (211,704). The AHA has published a scientific statement about this condition (705).

There is no widely accepted nomenclature for HF syndromes requiring hospitalization. Patients are described as having “acute HF,” “acute HF syndromes,” or “acute(ly) decompensated HF”; while the third has gained greatest acceptance, it too has limitations, for it does not make the important distinction between those with a de novo presentation of HF from those with worsening of previously chronic stable HF.

Data from HF registries have clarified the profile of patients with HF requiring hospitalization (107,704,706,707). Characteristically, such patients are elderly or near elderly, equally male or female, and typically have a history of hypertension, as well as other medical comorbidities, including chronic kidney disease, hyponatremia, hematologic abnormalities, and chronic obstructive pulmonary disease (107,706,708–713). A relatively equal percentage of patients with acutely decompensated HF have impaired versus preserved LV systolic function (707,714,715); clinically, patients with preserved systolic function are older, more likely to be female, to have significant hypertension, and to have less CAD. The overall morbidity and mortality for both groups is high.

Hospitalized patients with HF can be classified into important subgroups. These include patients with acute coronary ischemia, accelerated hypertension and acutely decompensated HF, shock, and acutely worsening right HF. Patients who develop HF decompensation after surgical procedures also bear mention. Each of these various categories of HF has specific etiologic factors leading to decompensation, presentation, management, and outcomes.

Noninvasive modalities can be used to classify the patient with hospitalized HF. The history and physical examination allows estimation of a patient’s hemodynamic status, that is, the degree of congestion (“dry” versus “wet”), as well as the adequacy of their peripheral perfusion (“warm” versus “cold”) (716) (Figure 4). Chest x-ray is variably sensitive for the presence of interstitial or alveolar edema, even in the presence of elevated filling pressures. Thus, a normal chest x-ray does not exclude acutely decompensated HF (717). The utility of natriuretic peptides in patients with acutely decompensated HF has been described in detail in Section 6.3.1. Both BNP and NT-proBNP are useful for the identification or exclusion of acutely decompensated HF in dyspneic patients (247,249,250,718,719), particularly in the context of uncertain diagnosis (720–722). Other options for diagnostic evaluation of patients with suspected acutely decompensated HF, such as acoustic cardiography (723), bioimpedance vector monitoring (724), or noninvasive cardiac output monitoring (725) are not yet validated.

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Figure 4

Classification of patients presenting with acutely decompensated heart failure.

Adapted with permission from Nohria et al. (716).

8.2 Precipitating Causes of Decompensated HF: Recommendations

• 1. ACS precipitating acute HF decompensation should be promptly identified by ECG and serum biomarkers, including cardiac troponin testing, and treated optimally as appropriate to the overall condition and prognosis of the patient. (Level of Evidence: C)

• 2. Common precipitating factors for acute HF should be considered during initial evaluation, as recognition of these conditions is critical to guide appropriate therapy. (Level of Evidence: C)

ACS is an important cause of worsening or new-onset HF (726). Although acute ST-segment elevation myocardial infarction can be readily apparent on an ECG, other ACS cases may be more challenging to diagnose. Complicating the clinical scenario is that many patients with acute HF, with or without CAD, have serum troponin levels that are elevated (727).

However, many other patients may have low levels of detectable troponins not meeting criteria for an acute ischemic event (278,728). Registry data have suggested that the use of coronary angiography is low for patients hospitalized with decompensated HF, and opportunities to diagnose important CAD may be missed (729). For the patient with newly discovered HF, clinicians should always consider the possibility that CAD is an underlying cause of HF (726).

Besides ACS, several other precipitating causes of acute HF decompensation must be carefully assessed to inform appropriate treatment, optimize outcomes, and prevent future acute events in patients with HF (730). See list below.

8.3 Maintenance of GDMT During Hospitalization: Recommendations

• 1. In patients with HFrEF experiencing a symptomatic exacerbation of HF requiring hospitalization during chronic maintenance treatment with GDMT, it is recommended that GDMT be continued in the absence of hemodynamic instability or contraindications (195,735,736). (Level of Evidence: B)

• 2. Initiation of beta-blocker therapy is recommended after optimization of volume status and successful discontinuation of intravenous diuretics, vasodilators, and inotropic agents. Beta-blocker therapy should be initiated at a low dose and only in stable patients. Caution should be used when initiating beta blockers in patients who have required inotropes during their hospital course (195,735,736). (Level of Evidence: B)

The patient’s maintenance HF medications should be carefully reviewed on admission, and it should be decided whether adjustments should be made as a result of the hospitalization. In the majority of patients with HFrEF who are admitted to the hospital, oral HF therapy should be continued, or even uptitrated, during hospitalization. It has been demonstrated that continuation of ACE inhibitors or ARBs and beta blockers for most patients is well tolerated and results in better outcomes (195,735,736). Withholding of, or reduction in, beta-blocker therapy should be considered only in patients hospitalized after recent initiation or increase in beta-blocker therapy or with marked volume overload or marginal/low cardiac output. Patients admitted with significant worsening of renal function should be considered for a reduction in, or temporary discontinuation of ACE inhibitors, ARBs, and/or aldosterone antagonists until renal function improves. Although it is important to ensure that evidence-based medications are instituted before hospital discharge, it is equally critical to reassess medications on admission and adjust their administration in light of the worsening HF.

8.4 Diuretics in Hospitalized Patients: Recommendations

• 1. Patients with HF admitted with evidence of significant fluid overload should be promptly treated with intravenous loop diuretics to reduce morbidity (737,738). (Level of Evidence: B)

• 2. If patients are already receiving loop diuretic therapy, the initial intravenous dose should equal or exceed their chronic oral daily dose and should be given as either intermittent boluses or continuous infusion. Urine output and signs and symptoms of congestion should be serially assessed, and the diuretic dose should be adjusted accordingly to relieve symptoms, reduce volume excess, and avoid hypotension (739). (Level of Evidence: B)

• 3. The effect of HF treatment should be monitored with careful measurement of fluid intake and output, vital signs, body weight that is determined at the same time each day, and clinical signs and symptoms of systemic perfusion and congestion. Daily serum electrolytes, urea nitrogen, and creatinine concentrations should be measured during the use of intravenous diuretics or active titration of HF medications. (Level of Evidence: C)

• 1. When diuresis is inadequate to relieve symptoms, it is reasonable to intensify the diuretic regimen using either:

  • a. higher doses of intravenous loop diuretics (38,739) (Level of Evidence: B); or

  • b. addition of a second (e.g., thiazide) diuretic (740–743). (Level of Evidence: B).

• 1. Low-dose dopamine infusion may be considered in addition to loop diuretic therapy to improve diuresis and better preserve renal function and renal blood flow (744,745). (Level of Evidence: B)

Patients with significant fluid overload should be initially treated with loop diuretics given intravenously during hospitalization. Therapy should begin in the emergency department without delay, as early therapy has been associated with better outcomes (37,738). Patients should be carefully monitored, including serial evaluation of volume status and systemic perfusion. Monitoring of daily weight, supine and standing vital signs, and fluid input and output is necessary for daily management. Assessment of daily electrolytes and renal function should be performed while intravenous diuretics are administered or HF medications are actively titrated. Intravenous loop diuretics have the potential to reduce glomerular filtration rate, further worsen neurohumoral activation, and produce electrolyte disturbances. Thus, although the use of diuretics may relieve symptoms, their impact on mortality has not been well studied. Diuretics should be administered at doses sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both. Because loop diuretics have a relatively short half-life, sodium reabsorption in the tubules will occur once the tubular concentration of the diuretics declines. Therefore, limiting sodium intake and dosing the diuretic continuously or multiple times per day will enhance diuretic effectiveness (434,737,746–748).

Some patients may present with moderate to severe renal dysfunction such that the diuretic response may be blunted, necessitating higher initial diuretic doses. In many cases, reduction of fluid overload may improve congestion and improve renal function, particularly if significant venous congestion is reduced (749). Clinical experience suggests it is difficult to determine whether congestion has been adequately treated in many patients, and registry data have confirmed that patients are frequently discharged after a net weight loss of only a few pounds. Although patients may rapidly improve symptomatically, they may remain congested or hemodynamically compromised. Routine use of serial natriuretic peptide measurement or Swan-Ganz catheter has not been conclusively shown to improve outcomes among these patients. Nevertheless, careful evaluation of all physical findings, laboratory parameters, weight change, and net fluid change should be considered before discharge.

When a patient does not respond to initial intravenous diuretics, several options may be considered. Efforts should be made to make certain that congestion persists and that another hemodynamic profile or alternate disease process is not evident. If there is doubt about the fluid status, consideration should be given for assessment of filling pressures and cardiac output using right-heart catheterization. If volume overload is confirmed, the dose of the loop diuretic should be increased to ensure that adequate drug levels reach the kidney. Adding a second diuretic, typically a thiazide, can improve diuretic responsiveness (435,442,443). Theoretically, continuous diuretic infusion may enhance diuresis because continuous diuretic delivery to the nephron avoids rebound sodium and fluid reabsorption (440,441,750,751). However, the DOSE (Diuretic Optimization Strategies Evaluation) trial did not find any significant difference between continuous infusion versus intermittent bolus strategies for symptoms, diuresis, or outcomes (739). It is reasonable to try an alternate approach of using either bolus or continuous infusion therapy different from the initial strategy among patients who are resistant to diuresis. Finally, some data suggest that low-dose dopamine infusion in addition to loop diuretics may improve diuresis and better preserve renal function, although ongoing trials will provide further data on this effect (744).

See Online Data Supplement 17 for additional data on diuretics.

8.5 Renal Replacement Therapy—Ultrafiltration: Recommendations

• 1. Ultrafiltration may be considered for patients with obvious volume overload to alleviate congestive symptoms and fluid weight (752). (Level of Evidence: B)

• 2. Ultrafiltration may be considered for patients with refractory congestion not responding to medical therapy. (Level of Evidence: C)

If all diuretic strategies are unsuccessful, ultrafiltration may be considered. Ultrafiltration moves water and small- to medium-weight solutes across a semipermeable membrane to reduce volume overload. Because the electrolyte concentration is similar to plasma, relatively more sodium can be removed than by diuretics (753–755). Initial studies supporting use of ultrafiltration in HF were small but provided safety and efficacy data in acute HF (755–757). Use of ultrafiltration in HF has been shown to reduce neurohormone levels and increase diuretic responsiveness. In a larger trial of 200 unselected patients with acute HF, ultrafiltration did reduce weight compared with bolus or continuous diuretics at 48 hours, had similar effects on the dyspnea score compared with diuretics, and improved readmission rate at 90 days (752). A randomized acute HF trial in patients with cardiorenal syndrome and persistent congestion has failed to demonstrate a significant advantage of ultrafiltration over bolus diuretic therapy (758,759). Cost, the need for veno-venous access, provider experience, and nursing support remain concerns about the routine use of ultrafiltration. Consultation with a nephrologist is appropriate before initiating ultrafiltration, especially in circumstances where the non-nephrology provider does not have sufficient experience with ultrafiltration.

See Online Data Supplements 17 and 38 for additional data on diuretics versus ultrafiltration in acute decompensated HF and worsening renal function and mortality.

8.6 Parenteral Therapy in Hospitalized HF: Recommendation

• 1. If symptomatic hypotension is absent, intravenous nitroglycerin, nitroprusside, or nesiritide may be considered an adjuvant to diuretic therapy for relief of dyspnea in patients admitted with acutely decompensated HF (760–763). (Level of Evidence: A)

The different vasodilators include 1) intravenous nitroglycerin, 2) sodium nitroprusside, and 3) nesiritide.

Intravenous nitroglycerin acts primarily through venodilation, lowers preload, and may help to rapidly reduce pulmonary congestion (764,765). Patients with HF and hypertension, coronary ischemia, or significant mitral regurgitation are often cited as ideal candidates for the use of intravenous nitroglycerin. However, tachyphylaxis to nitroglycerin may develop within 24 hours, and up to 20% of those with HF may develop resistance to even high doses (766–768).

Sodium nitroprusside is a balanced preload-reducing venodilator and afterload-reducing arteriodilator that also dilates the pulmonary vasculature (769). Data demonstrating efficacy are limited, and invasive hemodynamic blood pressure monitoring (such as an arterial line) is typically required; in such cases, blood pressure and volume status should be monitored frequently. Nitroprusside has the potential for producing marked hypotension and is usually used in the intensive care setting as well; longer infusions of the drug have been rarely associated with thiocyanate toxicity, particularly in the setting of renal insufficiency. Nitroprusside is potentially of value in severely congested patients with hypertension or severe mitral valve regurgitation complicating LV dysfunction.

Nesiritide (human BNP) reduces LV filling pressure but has variable effects on cardiac output, urinary output, and sodium excretion. An initial study demonstrated that the severity of dyspnea is reduced more rapidly compared with diuretics alone (760). A large randomized trial in patients with acute decompensated HF demonstrated nesiritide had no impact on mortality, rehospitalization, or renal function, a small but statistically significant impact on dyspnea, and an increased risk of hypotension (762). Because nesiritide has a longer effective half-life than nitroglycerin or nitroprusside, adverse effects such as hypotension may persist longer. Overall, presently there are no data that suggest that intravenous vasodilators improve outcomes in the patient hospitalized with HF; as such, use of intravenous vasodilators is limited to the relief of dyspnea in the hospitalized HF patient with intact blood pressure. Administration of intravenous vasodilators in patients with HFpEF should be done with caution because these patients are typically more volume sensitive.

The use of inotropic support as indicated for hospitalized HF with shock or impending shock and/or end-organ perfusion limitations is addressed in Section 7.4.4. See Table 26 for drug therapies and Online Data Supplements 32 and 33 for additional information on inotropic support.

See Online Data Supplement 39 for additional data on nesiritide.

8.7 Venous Thromboembolism Prophylaxis in Hospitalized Patients: Recommendation

• 1. A patient admitted to the hospital with decompensated HF should receive venous thromboembolism prophylaxis with an anticoagulant medication if the risk–benefit ratio is favorable (21,770). (Level of Evidence: B)

HF has long been recognized as affording additional risk for venous thromboembolic disease, associated with a number of pathophysiologic changes, including reduced cardiac output, increased systemic venous pressure, and chemical changes promoting blood clotting. When patients are hospitalized for decompensated HF or when patients with chronic stable HF are hospitalized for other reasons, they are at increased risk for venous thromboembolic disease, although accurate numerical estimates are lacking in the literature.

Most early data on the effectiveness of different anticoagulant regimens to reduce the incidence of venous thromboembolic disease in hospitalized patients were either observational, retrospective reports (776,777) or prospective studies using a variety of drugs and differing definitions of therapeutic effect and endpoints (774,778–780), making summary conclusions difficult. Early studies involved patients with far longer hospital lengths of stay than occur presently and were performed well before present standard-of-care treatments and diagnostic tests were available (774,778–780). Newer trials using presently available antithrombotic drugs often were not limited to patients with HF but included those with other acute illnesses, severe respiratory diseases, or simply a broad spectrum of hospitalized medical patients (771–774,781). In most studies, patients were categorized as having HF by admitting diagnosis, clinical signs, or functional class, whereas only 1 study (782) provided LVEF data on enrolled study patients. All included trials tried to exclude patients perceived to have an elevated risk of bleeding complications or with an elevated risk of toxicity from the specific agent tested (e.g., enoxaparin in patients with compromised renal function). Patients with HF typically made up a minority of the study cohort, and significance of results were not always reported by the authors, making ACCF/AHA class I recommendations difficult to support using this guideline methodology. In some trials, concurrent aspirin was allowed but not controlled for as a confounding variable (772,783).

For patients admitted specifically for decompensated HF and with adequate renal function (serum creatinine <2.0 mg/dL), randomized trials suggest that enoxaparin 40 mg subcutaneously once daily (770,773,774,783) or unfractionated heparin 5,000 units subcutaneously every 8 hours (771) will reduce radiographically demonstrable venous thrombosis. Effects on mortality or clinically significant pulmonary embolism rates are unclear. Lower doses of enoxaparin do not appear superior to placebo (770,773), whereas continuing weight-based enoxaparin therapy up to 3 months after hospital discharge does not appear to provide additional benefit (782).

A single prospective study failed to demonstrate certoparin to be noninferior to unfractionated heparin (783), whereas retrospective analysis of a prospective trial of dalteparin was underpowered to determine benefit in its HF cohort (776). Fondaparinux failed to show significant difference from placebo in an RCT that included a subgroup of 160 patients with HF (781).

No adequate trials have evaluated anticoagulant benefit in patients with chronic but stable HF admitted to the hospital for other reasons. However, the MEDENOX (Medical Patients with Enoxaparin) trial suggested that the benefit of enoxaparin may extend to this population (770,773,774).

A systematic review (784) failed to demonstrate prophylactic efficacy of graded compression stockings in general medical patients, but significant cutaneous complications were associated with their use. No studies were performed exclusively on patients with HF. Two RCTs in patients with stroke found no efficacy of these devices (785,786).

See Online Data Supplement 20 for additional data on anticoagulation.

8.8 Arginine Vasopressin Antagonists: Recommendation

• 1. In patients hospitalized with volume overload, including HF, who have persistent severe hyponatremia and are at risk for or having active cognitive symptoms despite water restriction and maximization of GDMT, vasopressin antagonists may be considered in the short term to improve serum sodium concentration in hypervolemic, hyponatremic states with either a V₂ receptor selective or a nonselective vasopressin antagonist (787,788). (Level of Evidence: B)

Even mild hyponatremia may be associated with neurocognitive problems, including falls and attention deficits (789). Treatment of hypervolemic hyponatremia with a V₂-selective vasopressin antagonist (tolvaptan) was associated with a significant improvement in the mental component of the Medical Outcomes Study Short Form General Health Survey (788). Hyponatremia may be treated with water restriction and maximization of GDMT that modulate angiotensin II, leading to improved renal perfusion and decreased thirst. Alternative causes of hyponatremia (e.g., syndrome of inappropriate antidiuretic hormone, hypothyroidism, and hypoaldosteronism) should be assessed. Vasopressin antagonists improve serum sodium in hypervolemic, hyponatremic states (787,788); however, longer-term therapy with a V₂-selective vasopressin antagonist did not improve mortality in patients with HF (790,791). Currently, 2 vasopressin antagonists are available for clinical use: conivaptan and tolvaptan. It may be reasonable to use a nonselective vasopressin antagonist to treat hyponatremia in patients with HF with cognitive symptoms due to hyponatremia. However, the long-term safety and benefit of this approach remains unknown. A summary of the recommendations for the hospitalized patient appears in Table 28.

8.9 Inpatient and Transitions of Care: Recommendations

See Table 29 for a summary of recommendations from this section.

• 1. The use of performance improvement systems and/or evidence-based systems of care is recommended in the hospital and early postdischarge outpatient setting to identify appropriate HF patients for GDMT, provide clinicians with useful reminders to advance GDMT, and assess the clinical response (82,365,706,792–796). (Level of Evidence: B)

• 2. Throughout the hospitalization as appropriate, before hospital discharge, at the first postdischarge visit, and in subsequent follow-up visits, the following should be addressed (204,795,797–799). (Level of Evidence: B):

  • a. initiation of GDMT if not previously established and not contraindicated;

  • b. precipitant causes of HF, barriers to optimal care transitions, and limitations in postdischarge support;

  • c. assessment of volume status and supine/upright hypotension with adjustment of HF therapy as appropriate;

  • d. titration and optimization of chronic oral HF therapy;

  • e. assessment of renal function and electrolytes where appropriate;

  • f. assessment and management of comorbid conditions;

  • g. reinforcement of HF education, self-care, emergency plans, and need for adherence; and

  • h. consideration for palliative care or hospice care in selected patients.

• 3. Multidisciplinary HF disease-management programs are recommended for patients at high risk for hospital readmission, to facilitate the implementation of GDMT, to address different barriers to behavioral change, and to reduce the risk of subsequent rehospitalization for HF (82,800–802). (Level of Evidence: B)

• 1. Scheduling an early follow-up visit (within 7 to 14 days) and early telephone follow-up (within 3 days) of hospital discharge are reasonable (101,803). (Level of Evidence: B)

• 2. Use of clinical risk-prediction tools and/or biomarkers to identify patients at higher risk for postdischarge clinical events are reasonable (215). (Level of Evidence: B)

Decisions about pharmacological therapies delivered during hospitalization likely can impact postdischarge outcome. Continuation or initiation of HF GDMT prior to hospital discharge is associated with substantially improved clinical outcomes for patients with HFrEF. However, caution should be used when initiating beta blockers in patients who have required inotropes during their hospital course or when initiating ACE inhibitors, ARBs, or aldosterone antagonists in those patients who have experienced marked azotemia or are at risk for hyperkalemia. The patient should be transitioned to oral diuretic therapy to verify its effectiveness. Similarly, optimal volume status should be achieved. Blood pressure should be adequately controlled, and, in patients with AF, ventricular response should also be well controlled. The hospitalization is a “teachable moment” to reinforce patient and family education and develop a plan of care, which should be communicated to the appropriate healthcare team.

Safety for patients hospitalized with HF is crucial. System changes necessary to achieve safer care include the adoption by all U.S. hospitals of a standardized set of 30 “Safe Practices” endorsed by the National Quality Forum (804) and National Patient Safety Goals espoused by The Joint Commission (805). Improved communication between clinicians and nurses, medication reconciliation, carefully planned transitions between care settings, and consistent documentation are examples of patient safety standards that should be ensured for patients with HF discharged from the hospital.

The prognosis of patients hospitalized with HF, and especially those with serial readmissions, is suboptimal. Hence, appropriate levels of symptomatic relief, support, and palliative care for patients with chronic HF should be addressed as an ongoing key component of the plan of care, especially when patients are hospitalized with acute decompensation (806). The appropriateness of discussion about advanced therapy or end-of-life preferences is reviewed in Section 11.

For patients with HF, the transition from inpatient to outpatient care can be an especially vulnerable period because of the progressive nature of the disease state, complex medical regimens, the large number of comorbid conditions, and the multiple clinicians who may be involved. Patient education and written discharge instructions or educational material given to the patient, family members, and/or caregiver during the hospital stay or at discharge to home are essential components of transition care. These should address all of the following: activity level, diet, discharge medications, follow-up appointment, weight monitoring, and what to do if symptoms worsen (297). Thorough discharge planning that includes special emphasis on ensuring adherence to an evidence-based medication regimen (795) is associated with improved patient outcomes (792,797,807). More intensive delivery of discharge instructions, coupled tightly with subsequent well-coordinated follow-up care for patients hospitalized with HF, has produced positive results in several studies (82,793,800). The addition of a 1-hour, nurse educator–delivered teaching session at the time of hospital discharge, using standardized instructions, resulted in improved clinical outcomes, increased self-care and treatment adherence, and reduced cost of care. Patients receiving the education intervention also had a lower risk of rehospitalization or death and lower costs of care (365). There are ongoing efforts to further develop evidence-based interventions in this population.

Transitional care extends beyond patient education. Care information, especially changes in orders and new diagnostic information, must be transmitted in a timely and clearly understandable form to all of the patient’s clinicians who will be delivering follow-up care. Other important components of transitional care include preparation of the patient and caregiver for what to expect at the next site of care, reconciliation of medications, follow-up plans for outstanding tests, and discussions about monitoring signs and symptoms of worsening conditions. Early outpatient follow-up, a central element of transitional care, varies significantly across U.S. hospitals. Early postdischarge follow-up may help minimize gaps in understanding of changes to the care plan or knowledge of test results and has been associated with a lower risk of subsequent rehospitalization (803). A follow-up visit within 7 to 14 days and/or a telephone follow-up within 3 days of hospital discharge are reasonable goals of care.

See Online Data Supplement 40 for additional data on oral medications for the hospitalized patient.

9.1 Atrial Fibrillation§

Patients with HF are more likely than the general population to develop AF (808). There is a direct relationship between the NYHA class and prevalence of AF in patients with HF progressing from 4% in those who are NYHA class I to 40% in those who are NYHA class IV (809). AF is also a strong independent risk factor for subsequent development of HF (376,808). In addition to those with HFrEF, patients with HFpEF are also at greater risk for AF than the general age-matched population (811). HF and AF can interact to promote their perpetuation and worsening through mechanisms such as rate-dependent worsening of cardiac function, fibrosis, and activation of neurohumoral vasoconstrictors. AF can worsen symptoms in patients with HF, and, conversely, worsened HF can promote a rapid ventricular response in AF.

Similar to other patient populations, for those with AF and HF, the main goals of therapy are prevention of thromboembolism and symptom control. Most patients with AF and HF would be expected to be candidates for systemic anticoagulation unless otherwise contraindicated. General principles of management include correction of underlying causes of AF and HF as well as optimization of HF management (Table 30). As in other patient populations, the issue of rate control versus rhythm control has been investigated. For patients who develop HF as a result of AF, a rhythm control strategy should be pursued. It is important to recognize that AF with a rapid ventricular response is one of the few potentially reversible causes of HF. Because of this, a patient who presents with newly detected HF in the presence of AF with a rapid ventricular response should be presumed to have a rate-related cardiomyopathy until proved otherwise. In this situation, 2 strategies can be considered. One is rate control of the patient’s AF and see if HF and EF improve. The other is to try to restore and maintain sinus rhythm. In this situation, it is common practice to initiate amiodarone and then arrange for cardioversion 1 month later. Amiodarone has the advantage of being both an effective rate-control medication and the most effective antiarrhythmic medication with a lower risk of proarrhythmic effect.

In patients with HF who develop AF, a rhythm-control strategy has not been shown to be superior to a rate-control strategy (812). If rhythm control is chosen, limited data suggest that AF catheter ablation in HF patients may lead to improvement in LV function and quality of life but is less likely to be effective than in patients with intact cardiac function (813,814). Because of their favorable effect on morbidity and mortality in patients with systolic HF, beta-adrenergic blockers are the preferred agents for achieving rate control unless otherwise contraindicated. Digoxin may be an effective adjunct to a beta blocker. The nondihydropyridine calcium antagonists, such as diltiazem, should be used with caution in those with depressed EF because of their negative inotropic effect. For those with HFpEF, nondihydropyridine calcium antagonists can be effective for achieving rate control but may be more effective when used in combination with digoxin. For those for whom a rate-control strategy is chosen, when rate control cannot be achieved either because of drug inefficacy or intolerance, atrioventricular node ablation and CRT device placement can be useful (78,116,595,596). See Figures 5 and 6 for AF treatment algorithms.

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Figure 5

Pharmacological management of patients with newly discovered AF. AF indicates atrial fibrillation; and HF, heart failure.

Reproduced from Fuster et al. (6).

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Figure 6

Pharmacological management of patients with recurrent paroxysmal AF. AF indicates atrial fibrillation.

Reproduced from Fuster et al. (6).

See Online Data Supplement 41 for additional data on AF.

9.2 Anemia

Anemia is a common finding in patients with chronic HF. Although variably reported, in part due to the lack of consensus on the definition of anemia, the prevalence of anemia among patients with HF increases with HF severity. Anemia is also more common in women and is seen in both patients with HFrEF and HFpEF (818–823). The World Health Organization defines anemia as a hemoglobin level of <12 g/dL in women and <13 g/dL in men. Registries have reported anemia to be present in 25% to 40% of HF patients (818–820). Anemia is associated with an increased mortality risk in HF. In a large study of >150,000 patients, the mor-tality risk was approximately doubled in anemic HF patients compared with those without anemia, and this risk persisted after controlling for other confounders, including renal dysfunction and HF severity (818). Anemia is also associated with reduced exercise capacity, impaired HRQOL, and a higher risk for hospitalization (225,819,824,825). These risks are inversely and linearly associated with hemoglobin levels, although a U-shaped risk with the highest hemoglobin levels has been reported (822,826).

Multiple etiological factors, many of which coexist within individual patients, contribute to the development of anemia in HF. Anemia in patients with HF is often normocytic and accompanied by an abnormally low reticulocyte count (825,827). Evaluation of anemia in HF requires careful consideration of other causes, the most common being secondary causes of iron deficiency anemia.

In persons without identifiable causes of anemia, erythropoiesis-stimulating agents have gained significant interest as potential adjunctive therapy in the patient with HF. In a retrospective study of erythropoiesis-stimulating agents in 26 patients with HF and anemia, the hemoglobin level, LVEF, and functional class improved (828). These patients required lower diuretic doses and were hospitalized less often. Similar findings were also observed in a randomized open-label study of 32 patients (829). A single-blind RCT showed that erythropoietin increased hemoglobin, peak oxygen uptake, and exercise duration in patients with severe HF and anemia (830). Two further studies confirmed these findings; however, none of these were double blind (831,832).

These positive data led to 2 larger studies. A 165-patient study showed that darbepoetin alfa was associated with improvement in several HRQOL measures with a trend toward improved exercise capacity (6-minute walking distance +34±7 m versus +11±10 m, P=0.074) (833). In STAMINA-HeFT (Study of Anemia in Heart Failure Trial), 319 patients were randomly assigned to darbepoetin alfa or placebo for 12 months (834). Although darbepoetin alfa did not improve exercise duration, it was well tolerated, and a trend toward improvement in the composite endpoint of all-cause mortality or first hospitalization for HF was seen (hazard ratio: 0.68; 95% confidence interval: 0.43 to 1.08; P=0.10) (834). These favorable data led to the design and initiation of the RED-HF (Phase III Reduction of Events With Darbepoetin alfa in Heart Failure) trial (835).

Two trials in erythropoiesis-stimulating agents, however, later raised concerns that patients treated with an erythropoiesis-stimulating agent may have an increased risk of cardiovascular events (836,837). Because the populations in these trials differed, the RED-HF trial was continued. Nevertheless, at the completion of the trial, the investigators concluded that treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic HF and mild-to-moderate anemia (838). Finally, a trial using intravenous iron as a supplement in patients with HFrEF with iron deficiency showed an improvement in functional status (840). There were no untoward adverse effects of iron in this trial. In the absence of a definitive evidence base, the writing committee has deferred a specific treatment recommendation regarding anemia.

9.3 Depression

Depression is common in patients with HF; those with depressive symptoms have lower HRQOL, poorer self-care, worse clinical outcomes, and more use of healthcare services (841–843). Although it might be assumed that depression occurs only among hospitalized patients (844), a multicenter study demonstrated that even at least 3 months after a hospitalization, 63% of patients with HF reported symptoms of depression (845). Potential pathophysiologic mechanisms proposed to explain the high prevalence of depression in HF include autonomic nervous system dysfunction, inflammation, cardiac arrhythmias, and altered platelet function, but the mechanism remains unclear (846). Although remission from depression may improve cardiovascular outcomes, the most effective intervention strategy is not yet known (842).

9.4 Other Multiple Comorbidities

Although there are additional and important comorbidities that afflict patients with HF as shown in Table 31, how best to generate specific recommendations remains uncertain, given the status of current evidence.

11.1 Coordinating Care for Patients With Chronic HF: Recommendations

• 1. Effective systems of care coordination with special attention to care transitions should be deployed for every patient with chronic HF that facilitate and ensure effective care that is designed to achieve GDMT and prevent hospitalization (80,82,793,870–884). (Level of Evidence: B)

• 2. Every patient with HF should have a clear, detailed, and evidence-based plan of care that ensures the achievement of GDMT goals, effective management of comorbid conditions, timely follow-up with the healthcare team, appropriate dietary and physical activities, and compliance with secondary prevention guidelines for cardiovascular disease. This plan of care should be updated regularly and made readily available to all members of each patient’s healthcare team (13). (Level of Evidence: C)

• 3. Palliative and supportive care is effective for patients with symptomatic advanced HF to improve quality of life (30,885–888). (Level of Evidence: B)

Education, support, and involvement of patients with HF and their families are critical and often complex, especially during transitions of care. Failure to understand and follow a detailed and often nuanced plan of care likely contributes to the high rates of HF 30-day rehospitalization and mortality seen across the United States (61,889). One critical intervention to ensure effective care coordination and transition is the provision of a comprehensive plan of care, with easily understood, culturally sensitive, and evidence-based educational materials, to patients with HF and/or caregivers during both hospital and office-based encounters. A comprehensive plan of care should promote successful patient self-care (870,884,890). Hence, the plan of care for patients with HF should continuously address in detail a number of complex issues, including adherence to GDMT, timely follow-up with the healthcare professionals who manage the patient’s HF and associated comorbidities, appropriate dietary and physical activities, including cardiac rehabilitation, and adherence to an extensive list of secondary prevention recommendations based on established guidelines for cardiovascular disease (Table 34). Clinicians must maintain vigilance about psychosocial, behavioral, and socioeconomic issues that patients with HF and their caregivers face, including access to care, risk of depression, and healthcare disparities (639,891–895). For example, patients with HF who live in skilled nursing facilities are at higher risk for adverse events, with a 1-year mortality rate >50% (896). Furthermore, community-dwelling patients with HF are often unable to afford the large number of medications prescribed, thereby leading to suboptimal medication adherence (897).

11.2 Systems of Care to Promote Care Coordination for Patients With Chronic HF

Improved communication between clinicians and nurses, medication reconciliation, carefully planned transitions between care settings, and consistent documentation are examples of patient safety standards that should be ensured for all patients with HF. The National Quality Forum has also endorsed a set of patient-centered “Preferred Practices for Care Coordination,” (898) which detail comprehensive specifications for successful care coordination for patients and their families.

Systems of care designed to support patients with HF and other cardiac diseases can produce a significant improvement in outcomes. Furthermore, the Centers for Medicare and Medicaid Services is now financially penalizing hospitals for avoidable hospitalizations and readmissions, thereby emphasizing the importance of such systems-based care coordination of patients with HF (899). However, the quality of evidence is mixed for specific components of HF clinical management interventions, such as home-based care (871,872), disease management (873,874,880), and remote telemonitoring programs (80,875,876,878). Unfortunately, numerous and nonstandardized definitions of disease management (873,879,880), including the specific elements that compose disease management, impede efforts to improve the care of patients with HF. Hence, more generic multidisciplinary strategies for improving the quality and cost-effectiveness of systems-based HF care should be evaluated with equal weight to those interventions focused on improving adherence to GDMT. For example, multidisciplinary approaches can reduce rates of hospitalization for HF. Programs involving specialized follow-up by a multidisciplinary team decrease all-cause hospitalizations and mortality; however, this has not been shown for “disease management programs” that focus only on self-care activities (82,793,881,882,900). Furthermore, patient characteristics may be important predictors of HF and other cardiac disease–related survival and hospitalization. Overall, very few specific interventions have been consistently identified and successfully applied in clinical practice (204,214,901–903).

See Online Data Supplements 42 and 43 for additional data on disease management and telemonitoring.

11.3 Palliative Care for Patients With HF

The core elements of comprehensive palliative care for HF delivered by clinicians include expert symptom assessment and management. Ongoing care should address symptom control, psychosocial distress, HRQOL, preferences about end-of-life care, caregiver support, and assurance of access to evidence-based disease-modifying interventions. The HF team can help patients and their families explore treatment options and prognosis. The HF and palliative care teams are best suited to help patients and families decide when end-of-life care (including hospice) is appropriate (30,885–888,904). Assessment for frailty and dementia is part of this decision care process offered to the patient and family.

Data suggest that advance directives specifying limitations in end-of-life care are associated with significantly lower levels of Medicare spending, lower likelihood of in-hospital death, and higher use of hospice care in regions characterized by higher levels of end-of-life spending (905). In newly diagnosed cancer patients, palliative care interventions delivered early have had a positive impact on survival and HRQOL. This approach may also be relevant for HF (906). Access to formally trained palliative care specialists may be limited in ambulatory settings. Therefore, cardiologists, primary care physicians, physician assistants, advanced practice nurses, and other members of the HF healthcare team should be familiar with these local treatment options. Evaluation for cardiac transplantation or MCS in experienced centers should include formal palliative care consultation, which can improve advanced care planning and enhance the overall quality of decision making and integrated care for these patients, regardless of the advanced HF therapy selected (907).

American College of Cardiology Foundation

John Gordon Harold, MD, MACC, President

Shalom Jacobovitz, Chief Executive Officer

William J. Oetgen, MD, MBA, FACC, Senior Vice President, Science and Quality

Charlene L. May, Senior Director, Science and Clinical Policy

American College of Cardiology Foundation/American Heart Association

Lisa Bradfield, CAE, Director, Science and Clinical Policy

Debjani Mukherjee, MPH, Associate Director, Evidence-Based Medicine

Ezaldeen Ramadhan III, Specialist, Science and Clinical Policy

Sarah Jackson, MPH, Specialist, Science and Clinical Policy

American Heart Association

Donna K. Arnett, PhD, MD, FAHA, President

Nancy Brown, Chief Executive Officer

Rose Marie Robertson, MD, FAHA, Chief Science Officer

Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations

Judy Bezanson, DSN, RN, CNS-MS, FAHA, Science and Medicine Advisor

Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations