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(Circulation. 2005;112:1825-1852.)
© 2005 American Heart Association, Inc.

ACC/AHA Practice Guidelines

ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult—Summary Article

A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society

WRITING COMMITTEE: Sharon Ann Hunt, MD, FACC, FAHA, Chair; William T. Abraham, MD, FACC, FAHA; Marshall H. Chin, MD, MPH, FACP; Arthur M. Feldman, MD, PhD, FACC, FAHA; Gary S. Francis, MD, FACC, FAHA; Theodore G. Ganiats, MD; Mariell Jessup, MD, FACC, FAHA; Marvin A. Konstam, MD, FACC; Donna M. Mancini, MD; Keith Michl, MD, FACP; John A. Oates, MD, FAHA; Peter S. Rahko, MD, FACC, FAHA; Marc A. Silver, MD, FACC, FAHA; Lynne Warner Stevenson, MD, FACC, FAHA; Clyde W. Yancy, MD, FACC, FAHA

TASK FORCE MEMBERS: Elliott M. Antman, MD, FACC, FAHA, Chair; Sidney C. Smith, Jr, MD, FACC, FAHA, Vice-Chair; Cynthia D. Adams, MSN, APRN-BC, FAHA; Jeffrey L. Anderson, MD, FACC, FAHA; David P. Faxon, MD, FACC, FAHA^*; Valentin Fuster, MD, PhD, FACC, FAHA, FESC^*; Jonathan L. Halperin, MD, FACC, FAHA; Loren F. Hiratzka, MD, FACC, FAHA; Sharon Ann Hunt, MD, FACC, FAHA; Alice K. Jacobs, MD, FACC, FAHA; Rick Nishimura, MD, FACC, FAHA; Joseph P. Ornato, MD, FACC, FAHA; Richard L. Page, MD, FACC, FAHA; Barbara Riegel, DNSc, RN, FAHA

	Table of Contents

Top Table of Contents I. Introduction II. Characterization of HF... III. Initial and Serial... IV. Therapy V. Treatment of Special... VI. Patients With HF... VII. End-of Life Considerations VIII. Implementation of Practice... References

 

I. Introduction 1826

II. Characterization of HF as a Clinical Syndrome 1828

A. Definition of HF 1828

B. HF as a Symptomatic Disorder 1828

C. HF as a Progressive Disorder 1829

III. Initial and Serial Clinical Assessment of Patients Presenting With HF 1829

A. Initial Evaluation of Patients 1831

1. Identification of a Structural and Functional Abnormality 1831

2. Evaluation of the Cause of HF 1831

a. History and Physical Examination 1831

b. Laboratory Testing 1831

B. Ongoing Evaluation of Patients 1832

1. Assessment of Volume Status 1832

2. Laboratory Assessment 1832

3. Assessment of Prognosis 1832

IV. Therapy 1832

A. Patients at High Risk for Developing HF (Stage A) 1832

1. Control of Risk 1833

a. Treatment of Hypertension 1833

b. Treatment of Diabetes 1834

c. Management of the Metabolic Syndrome 1834

d. Management of Atherosclerotic Disease 1834

e. Control of Conditions That May Cause Cardiac Injury 1834

f. Other Measures 1834

2. Early Detection of Structural Abnormalities 1834

B. Patients With Cardiac Structural Abnormalities or Remodeling Who Have Not Developed HF Symptoms (Stage B) 1835

1. Prevention of Cardiovascular Events 1835

a. Patients With an Acute MI 1835

b. Patients With Chronic Reduction of LVEF but No Symptoms 1835

C. Patients With Current or Prior Symptoms of HF (Stage C) 1836

1. Patients With Reduced LVEF 1836

a. General Measures 1837

b. Drugs Recommended for Routine Use 1837

c. Interventions to be Considered for Use in Selected Patients 1842

d. Drugs and Interventions Under Active Investigation 1842

e. Drugs and Interventions of Unproved Value and Not Recommended 1842

2. Patients With HF and Normal LVEF 1843

a. Identification of Patients 1843

b. Diagnosis 1843

c. Principles of Treatment 1843

D. Patients With Refractory End-Stage HF (Stage D) 1844

1. Management of Fluid Status 1844

2. Intravenous Peripheral Vasodilators and Positive Inotropic Agents 1844

3. Mechanical and Surgical Strategies 1844

V. Treatment of Special Populations 1845

A. Women and Men 1845

B. Ethnic Considerations 1845

C. Elderly Patients 1845

VI. Patients With HF Who Have Concomitant Disorders 1846

A. Cardiovascular Disorders 1846

1. Hypertension, Hyperlipidemia, and Diabetes Mellitus 1846

2. Supraventricular Arrhythmias 1846

3. Prevention of Thromboembolic Events 1846

B. Noncardiovascular Disorders 1846

1. Patients With Pulmonary Disease 1846

2. Patients With Cancer 1847

3. Patients With Thyroid Disease 1847

4. Patients With Hepatitis C and Human Immunodeficiency Virus 1847

5. Patients With Anemia 1847

VII. End-of-Life Considerations 1847

VIII. Implementation of Practice Guidelines 1847

A. Performance Measures 1848

References 1848

	I. Introduction

Top Table of Contents I. Introduction II. Characterization of HF... III. Initial and Serial... IV. Therapy V. Treatment of Special... VI. Patients With HF... VII. End-of Life Considerations VIII. Implementation of Practice... References

 
The American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Practice Guidelines regularly reviews existing guidelines to determine when an update or full revision is needed. This process gives priority to areas where major changes in text, particularly recommendations, are required on the basis of new understanding of evidence. Minor changes in verbiage and references are discouraged. The ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult published in 2001 have now been updated. The full-text guidelines incorporating the updated material are e-published in the Journal of the American College of Cardiology and Circulation on the ACC Web site (www.acc.org) and the AHA Web site (www.americanheart.org) in 2 versions: a version highlighting the changes in recommendations (i.e., deleted text struck through, new text underlined) from the 2001 guideline to the 2005 guideline and a "clean" version that incorporates all changes in the recommendations. (The "track change" version only highlights changes to the recommendations; it does not show changes to supporting text, tables, or figures.) This article describes the major areas of change reflected in the update. Please note we have changed the Table of Contents headings in the 2001 guidelines from roman numerals to unique identifying numbers. Interested readers are referred to the full-text guideline to completely understand the context of these changes.

Heart failure (HF) is a major and growing public health problem in the United States. Approximately 5 million patients in this country have HF, and more than 550 000 patients are diagnosed with HF for the first time each year ⁽¹⁾. The disorder is the primary reason for 12 to 15 million office visits and 6.5 million hospital days each year ⁽²⁾. From 1990 to 1999, the annual number of hospitalizations has increased from approximately 810 000 to over 1 million for HF as a primary diagnosis and from 2.4 to 3.6 million for HF as a primary or secondary diagnosis ⁽³⁾. In 2001, nearly 53 000 patients died of HF as a primary cause. The number of HF deaths has increased steadily despite advances in treatment, in part because of increasing numbers of patients with HF due to better treatment and "salvage" of patients with acute myocardial infarctions (MIs) earlier in life ⁽¹⁾.

Heart failure is primarily a condition of the elderly ⁽⁴⁾, and thus the widely recognized "aging of the population" also contributes to the increasing incidence of HF. The incidence of HF approaches 10 per 1000 population after age 65 ⁽¹⁾ and approximately 80% of patients hospitalized with HF are more than 65 years old ⁽⁵⁾. Heart failure is the most common Medicare diagnosis-related group (i.e., hospital discharge diagnosis), and more Medicare dollars are spent for the diagnosis and treatment of HF than for any other diagnosis ⁽⁶⁾. It has been estimated that in 2005, the total direct and indirect cost of HF in the United States will be equal to $27.9 billion ⁽¹⁾. In the United States, approximately $2.9 billion annually is spent on drugs for the treatment of HF ⁽¹⁾.

The ACC and the AHA first published guidelines for the evaluation and management of HF in 1995 ⁽⁷⁾ and published revised guidelines in 2001 ⁽⁸⁾. Since that time, a great deal of progress has been made in the development of both pharmacological and nonpharmacological approaches to treatment for this common, costly, disabling, and potentially fatal disorder. Available treatments have increased, but this increase has rendered clinical decision making far more complex. The timing and sequence of initiating treatments and the appropriateness of prescribing them in combination are uncertain. The increasing recognition of the existence of clinical HF in patients with a normal ejection fraction (EF) has also led to heightened awareness of the limitations of evidence-based therapy for this important group of patients. For these reasons, the 2 organizations believed that it was appropriate to reassess and update these guidelines, fully recognizing that the optimal therapy of HF remains a work in progress and that future advances will require that the guideline be updated again.

In formulating the 2001 document, the writing committee decided to take a new approach to the classification of HF, one that emphasized both the development and progression of the disease. In doing so, the 2001 document identified 4 stages involved in the development of the HF syndrome. The first 2 stages (A and B) are clearly not HF but are an attempt to help healthcare providers identify patients early who are at risk for developing HF. Stages A and B patients are best defined as those with risk factors that clearly predispose toward the development of HF. For example, patients with coronary artery disease, hypertension, or diabetes mellitus who do not yet demonstrate impaired left ventricular (LV) function, hypertrophy, or geometric chamber distortion would be considered Stage A, whereas patients who are asymptomatic but demonstrate LV hypertrophy (LVH) and/or impaired LV function would be designated as Stage B. Stage C then denotes patients with current or past symptoms of HF associated with underlying structural heart disease (the bulk of patients with HF), and Stage D designates patients with truly refractory HF who might be eligible for specialized, advanced treatment strategies such as mechanical circulatory support, procedures to facilitate fluid removal, continuous inotropic infusions, or cardiac transplantation or other innovative or experimental surgical procedures, or for end-of-life care, such as hospice.

This classification recognizes that there are established risk factors and structural prerequisites for the development of HF and that therapeutic interventions introduced even before the appearance of LV dysfunction or symptoms can reduce the population morbidity and mortality of HF. This classification system is intended to complement but in no way to replace the New York Heart Association (NYHA) functional classification, which primarily gauges the severity of symptoms in patients who are in Stage C or D. It has been recognized for many years that the NYHA functional classification reflects a subjective assessment by a healthcare provider and can change frequently over short periods of time. It has also been recognized that the treatments used may not differ significantly across the classes. Therefore, the committee believed that a staging system was needed that would reliably and objectively identify patients during the course of their developing disease and that would be linked to treatments uniquely appropriate at each stage of illness. According to this new staging approach, patients would only be expected to either not advance at all or to advance from one stage to the next, unless progression of the disease was slowed or stopped by treatment, and spontaneous reversal of this progression would be considered unusual. For instance, although symptoms (NYHA class) might vary widely over time (in response to therapy or to progression of disease) in a patient who has already developed the clinical syndrome of HF (Stage C), the patient could never return to Stage B (never had HF), and therapies recommended for Stage C will be appropriate even if this patient is in NYHA class I. This new classification scheme adds a useful dimension to our thinking about HF that is similar to that achieved by staging or risk assessment systems for other disorders (e.g., those used in the approach to cancer).

A classification of recommendation and level of evidence have been assigned to each recommendation. Classification of recommendations and levels of evidence are expressed in the ACC/AHA format as follows. Please refer to Table 1 in the full-text guidelines for more details.

View this table: [in this window] [in a new window]   TABLE 1. Evaluation of the Cause of Heart Failure: The History

Classification of Recommendations

Class I: Conditions for which there is evidence and/or general agreement that a given procedure/therapy is beneficial, useful, and/or effective.

Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure/therapy.

IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.

IIb: Usefulness/efficacy is less well established by evidence/opinion.

Class III: Conditions for which there is evidence and/or general agreement that a procedure/therapy is not useful/effective and in some cases may be harmful.

Level of Evidence

Level of Evidence A: Data are derived from multiple randomized clinical trials or meta-analyses.

Level of Evidence B: Data are derived from a single randomized trial, or nonrandomized studies.

Level of Evidence C: Only consensus opinion of experts, case studies, or standard of care.

This document focuses on the prevention of HF and on the evaluation and management of chronic HF in the adult patient with normal or reduced LVEF. It specifically did not consider acute HF, which might merit a separate set of guidelines and is addressed in part in the ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction ⁽⁹⁾ and the ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina and Non-ST Elevation Myocardial Infarction ⁽¹⁰⁾. We have also excluded HF in children, both because the underlying causes of HF in children differ from those in adults and because none of the controlled trials of treatments for HF have included children. We have not considered the management of HF due to primary valvular disease [see ACC/AHA Guidelines on the Management of Patients With Valvular Heart Disease ⁽¹¹⁾] or congenital malformations, and we have not included recommendations for the treatment of specific myocardial disorders (e.g., hemochromatosis, sarcoidosis, or amyloidosis).

The various therapeutic strategies described in this document can be viewed as a checklist to be considered for each patient in an attempt to individualize treatment for an evolving disease process. Every patient is unique, not only in terms of his or her cause and course of HF, but also in terms of his or her personal and cultural approach to the disease. Guidelines can only provide an outline for evidence-based decisions or recommendations for individual care; these guidelines are meant to provide that outline.

All of the recommendations in this guideline update were written in full sentences that express a complete thought, such that a recommendation, even if separated and presented apart from the rest of the document, would still convey the full intent of the recommendation. It is hoped that this will increase readers’ comprehension of the guidelines. The rewritten recommendations appear under their respective headings.

Use of boldfaced type in the recommendations shows where the intent of the recommendations has changed from the 2001 guidelines.

	II. Characterization of HF as a Clinical Syndrome

Top Table of Contents I. Introduction II. Characterization of HF... III. Initial and Serial... IV. Therapy V. Treatment of Special... VI. Patients With HF... VII. End-of Life Considerations VIII. Implementation of Practice... References

 
A. Definition of HF
Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. The cardinal manifestations of HF are dyspnea and fatigue, which may limit exercise tolerance, and fluid retention, which may lead to pulmonary congestion and peripheral edema. Both abnormalities can impair the functional capacity and quality of life of affected individuals, but they do not necessarily dominate the clinical picture at the same time. Some patients have exercise intolerance but little evidence of fluid retention, whereas others complain primarily of edema and report few symptoms of dyspnea or fatigue. Because not all patients have volume overload at the time of initial or subsequent evaluation, the term "heart failure" is preferred over the older term "congestive heart failure."

The clinical syndrome of HF may result from disorders of the pericardium, myocardium, endocardium, or great vessels, but the majority of patients with HF have symptoms due to an impairment of LV myocardial function. Heart failure may be associated with a wide spectrum of LV functional abnormalities, which may range from patients with normal LV size and preserved EF to those with severe dilatation and/or markedly reduced EF. In most patients, abnormalities of systolic and diastolic dysfunction coexist, regardless of EF. Patients with normal EF may have a different natural history and may require different treatment strategies than patients with reduced EF, although such differences remain controversial (see Section 4.3.2 in the full-text guidelines).

Coronary artery disease, hypertension, and dilated cardiomyopathy are the causes of HF in a substantial proportion of patients in the Western world. As many as 30% of patients with dilated cardiomyopathy may have a genetic cause ⁽¹²⁾. Valvular heart disease is still a common cause of HF. In fact, nearly any form of heart disease may ultimately lead to the HF syndrome.

It should be emphasized that HF is not equivalent to cardiomyopathy or to LV dysfunction; these latter terms describe possible structural or functional reasons for the development of HF. Instead, HF is defined as a clinical syndrome that is characterized by specific symptoms (dyspnea and fatigue) in the medical history and signs (edema, rales) on the physical examination. There is no single diagnostic test for HF because it is largely a clinical diagnosis that is based on a careful history and physical examination.

B. Heart Failure as a Symptomatic Disorder
The approach that is most commonly used to quantify the degree of functional limitation imposed by HF is one first developed by the NYHA. This system assigns patients to 1 of 4 functional classes, depending on the degree of effort needed to elicit symptoms: patients may have symptoms of HF at rest (class IV), on less-than-ordinary exertion (class III), on ordinary exertion (class II), or only at levels of exertion that would limit normal individuals (class I). Although the functional class tends to deteriorate over periods of time, most patients with HF do not typically show an uninterrupted and inexorable worsening of symptoms. Instead, the severity of symptoms characteristically fluctuates even in the absence of changes in medications, and changes in medications and diet can have either favorable or adverse effects on functional capacity in the absence of measurable changes in ventricular function. Some patients may demonstrate remarkable recovery, sometimes associated with improvement in structural and functional abnormalities. Usually, sustained improvement is associated with drug therapy, and that therapy should be continued indefinitely.

The mechanisms responsible for the exercise intolerance of patients with chronic HF have not been defined clearly. Although HF is generally regarded as a hemodynamic disorder, many studies have indicated that there is a poor relation between measures of cardiac performance and the symptoms produced by the disease. Patients with a very low EF may be asymptomatic, whereas patients with preserved LVEF may have severe disability. The apparent discordance between EF and the degree of functional impairment is not well understood but may be explained in part by alterations in ventricular distensibility, valvular regurgitation, pericardial restraint, cardiac rhythm, conduction abnormalities, and right ventricular function ⁽¹²⁾. In addition, in ambulatory patients, many noncardiac factors may contribute substantially to exercise intolerance. These factors include but are not limited to changes in peripheral vascular function, skeletal muscle physiology, pulmonary dynamics, neurohormonal and reflex autonomic activity, and renal sodium handling. The existence of these noncardiac factors may explain why the hemodynamic improvement produced by therapeutic agents in patients with chronic HF may not be immediately or necessarily translated into clinical improvement. Although pharmacological interventions may produce rapid changes in hemodynamic variables, signs and symptoms may improve slowly over weeks or months or not at all.

C. Heart Failure as a Progressive Disorder
Left ventricular dysfunction begins with some injury to, or stress on, the myocardium and is generally a progressive process, even in the absence of a new identifiable insult to the heart. The principal manifestation of such progression is a change in the geometry and structure of the LV, such that the chamber dilates and/or hypertrophies and becomes more spherical—a process referred to as cardiac remodeling. This change in chamber size and structure not only increases the hemodynamic stresses on the walls of the failing heart and depresses its mechanical performance but may also increase regurgitant flow through the mitral valve. These effects, in turn, serve to sustain and exacerbate the remodeling process. Cardiac remodeling generally precedes the development of symptoms (occasionally by months or even years), continues after the appearance of symptoms, and contributes substantially to worsening of symptoms despite treatment. Progression of coronary artery disease, diabetes mellitus, hypertension, or the onset of atrial fibrillation may also contribute to the progression of HF. The development of structural abnormalities can have 1 of 3 outcomes: 1) patients die before developing symptoms (in stage A or B), 2) patients develop symptoms controlled by treatment, or 3) patients die of progressive HF. Sudden death can interrupt this course at any time.

Although several factors can accelerate the process of LV remodeling, there is substantial evidence that the activation of endogenous neurohormonal systems plays an important role in cardiac remodeling and thereby in the progression of HF. Patients with HF have elevated circulating or tissue levels of norepinephrine, angiotensin II, aldosterone, endothelin, vasopressin, and cytokines, which can act (alone or in concert) to adversely affect the structure and function of the heart. These neurohormonal factors not only increase the hemodynamic stresses on the ventricle by causing sodium retention and peripheral vasoconstriction but may also exert direct toxic effects on cardiac cells and stimulate myocardial fibrosis, which can further alter the architecture and impair the performance of the failing heart. Neurohormonal activation also has direct deleterious effects on the myocytes and interstitium, altering the performance and phenotype of these cells.

The development of HF can be appropriately characterized by considering 4 stages of the disease, as described in the Introduction. This staging system recognizes that HF, like coronary artery disease, has established risk factors and structural prerequisites; that the development of HF has asymptomatic and symptomatic phases; and that specific treatments targeted at each stage can reduce the morbidity and mortality of HF (Figure).

View larger version (43K): [in this window] [in a new window]   Stages in the development of HF/recommended therapy by stage. FHx CM indicates family history of cardiomyopathy; ACEI, angiotensin converting enzyme inhibitors; and ARB, angiotensin receptor blocker.

Stages in the development of HF/recommended therapy by stage. FHx CM indicates family history of cardiomyopathy; ACEI, angiotensin converting enzyme inhibitors; and ARB, angiotensin receptor blocker.

	III. Initial and Serial Clinical Assessment of Patients Presenting With HF

Top Table of Contents I. Introduction II. Characterization of HF... III. Initial and Serial... IV. Therapy V. Treatment of Special... VI. Patients With HF... VII. End-of Life Considerations VIII. Implementation of Practice... References

 
In this section, recommendations for the evaluation of patients with HF have been separated into 2 sets of recommendations: 1) for the initial clinical assessment of patients presenting with HF and 2) for the serial clinical assessment of patients presenting with HF.

Recommendations for the Initial Clinical Assessment of Patients Presenting With Heart Failure Class I

1. A thorough history and physical examination should be obtained/performed in patients presenting with HF to identify cardiac and noncardiac disorders or behaviors that might cause or accelerate the development or progression of HF. (Level of Evidence: C)
   
2. A careful history of current and past use of alcohol, illicit drugs, current or past standard or "alternative therapies," and chemotherapy drugs should be obtained from patients presenting with HF. (Level of Evidence: C)
   
3. In patients presenting with HF, initial assessment should be made of the patient’s ability to perform routine and desired activities of daily living. (Level of Evidence: C)
   
4. Initial examination of patients presenting with HF should include assessment of the patient’s volume status, orthostatic blood pressure changes, measurement of weight and height, and calculation of body mass index. (Level of Evidence: C)
   
5. 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, fasting blood glucose (glycohemoglobin), lipid profile, liver function tests, and thyroid-stimulating hormone. (Level of Evidence: C)
   
6. Twelve-lead electrocardiogram and chest radiograph (PA and lateral) should be performed initially in all patients presenting with HF. (Level of Evidence: C)
   
7. Two-dimensional echocardiography with Doppler should be performed during initial evaluation of patients presenting with HF to assess LVEF, LV size, wall thickness, and valve function. Radionuclide ventriculography can be performed to assess LVEF and volumes. (Level of Evidence: C)
   
8. Coronary arteriography should be performed in patients presenting with HF who have angina or significant ischemia unless the patient is not eligible for revascularization of any kind. (Level of Evidence: B)
   

Class IIa

1. Coronary arteriography is reasonable for patients presenting with HF who have chest pain that may or may not be of cardiac origin who have not had evaluation of their coronary anatomy and who have no contraindications to coronary revascularization. (Level of Evidence: C)
   
2. Coronary arteriography is reasonable for patients presenting with HF who have known or suspected coronary artery disease but who do not have angina unless the patient is not eligible for revascularization of any kind. (Level of Evidence: C)
   
3. Noninvasive imaging to detect myocardial ischemia and viability is reasonable in patients presenting with HF who have known coronary artery disease and no angina unless the patient is not eligible for revascularization of any kind. (Level of Evidence: B)
   
4. Maximal exercise testing with or without measurement of respiratory gas exchange and/or blood oxygen saturation is reasonable in patients presenting with HF to help determine whether HF is the cause of exercise limitation when the contribution of HF is uncertain. (Level of Evidence: C)
   
5. Maximal exercise testing with measurement of respiratory gas exchange is reasonable to identify high-risk patients presenting with HF who are candidates for cardiac transplantation or other advanced treatments. (Level of Evidence: B)
   
6. Screening for hemochromatosis, sleep-disturbed breathing, or human immunodeficiency virus is reasonable in selected patients who present with HF. (Level of Evidence: C)
   
7. 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)
   
8. Endomyocardial biopsy can be useful in patients presenting with HF when a specific diagnosis is suspected that would influence therapy. (Level of Evidence: C)
   
9. Measurement of B-type natriuretic peptide (BNP^*) can be useful in the evaluation of patients presenting in the urgent care setting in whom the clinical diagnosis of HF is uncertain. (Level of Evidence: A)
   

Class IIb

1. No ninvasive imaging may be considered to define the likelihood of coronary artery disease in patients with HF and LV dysfunction. (Level of Evidence: C)
   
2. Holter monitoring might be considered in patients presenting with HF who have a history of MI and are being considered for electrophysiologic study to document VT inducibility. (Level of Evidence: C)
   

Class III

1. Endomyocardial biopsy should not be performed in the routine evaluation of patients with HF. (Level of Evidence: C)
   
2. Routine use of signal-averaged electrocardiography is not recommended for the evaluation of patients presenting with HF. (Level of Evidence: C)
   
3. Routine measurement of circulating levels of neurohormones (e.g., norepinephrine or endothelin) is not recommended for patients presenting with HF. (Level of Evidence: C)
   

Recommendations for Serial Clinical Assessment of Patients Presenting With HF Class I

1. Assessment should be made at each visit of the ability of a patient with HF to perform routine and desired activities of daily living. (Level of Evidence: C)
   
2. Assessment should be made at each visit of the volume status and weight of a patient with HF. (Level of Evidence: C)
   
3. Careful history of current use of alcohol, tobacco, illicit drugs, "alternative therapies," and chemotherapy drugs, as well as diet and sodium intake, should be obtained at each visit of a patient with HF. (Level of Evidence: C)
   

Class IIa

1. Repeat measurement of EF and the severity of structural remodeling can provide useful information in patients with HF who have had a change in clinical status or who have experienced or recovered from a clinical event or received treatment that might have had a significant effect on cardiac function. (Level of Evidence: C)
   

Class IIb

1. The value of serial measurements of BNP to guide therapy for patients with HF is not well established. (Level of Evidence: C)
   

A. Initial Evaluation of Patients
1. Identification of a Structural and Functional Abnormality
The single most useful diagnostic test in the evaluation of patients with HF is the comprehensive 2-dimensional echocardiogram coupled with Doppler flow studies to determine whether abnormalities of myocardium, heart valves, or pericardium are present and which chambers are involved. A comprehensive echocardiographic evaluation is important, because it is common for patients to have more than 1 cardiac abnormality that contributes to the development of HF. Furthermore, the study may serve as a baseline for comparison, because measurement of EF and the severity of structural remodeling can provide useful information in patients who have had a change in clinical status or who have experienced or recovered from a clinical event or received treatment that might have had a significant effect on cardiac function. Other tests such as radionuclide ventriculography or magnetic resonance imaging may also be used to provide information regarding the nature and severity of the cardiac abnormality.

2. Evaluation of the Cause of HF
a. History and Physical Examination
Evaluation of potential causative factors begins with a thorough history and careful physical examination (Table 1).

b. Laboratory Testing
Laboratory testing may reveal the presence of disorders or conditions that can lead to or exacerbate HF. The initial evaluation of patients with HF should include a complete blood count, urinalysis, serum electrolytes (including calcium and magnesium), glycohemoglobin, and blood lipids, as well as tests of both renal and hepatic function, a chest radiograph, and a 12-lead electrocardiogram. Thyroid-function tests (especially thyroid-stimulating hormone) should be measured, because both hyperthyroidism and hypothyroidism can be a primary or contributory cause of HF.

Several recent assays have been developed for BNP and related peptides. Several of the natriuretic peptides are synthesized by and released from the heart. Elevated plasma BNP levels have been associated with reduced LVEF ⁽¹³⁾, LVH, elevated LV filling pressures, and acute MI and ischemia, although they can occur in other settings, such as pulmonary embolism and chronic obstructive pulmonary disease. They are sensitive to other biological factors, such as age, sex, weight, and renal function ⁽¹⁴⁾. Elevated levels lend support to a diagnosis of abnormal ventricular function or hemodynamics causing symptomatic HF ⁽¹⁵⁾. Trials with this diagnostic marker suggest utility in the urgent-care setting, where it has been used in combination with clinical evaluation to differentiate dyspnea due to HF from dyspnea of other causes ^(13,16), and suggest that its use may reduce the time to hospital discharge and the cost of treatment ⁽¹⁷⁾. B-type natriuretic peptide levels tend to be less elevated in HF with preserved EF than in HF with low EF and are lower in obese patients ^(18,19). Levels of BNP may be meaningfully elevated in women and in people over 60 years of age who do not have HF, and thus BNP levels should be interpreted cautiously in such individuals when distinguishing between cardiac and noncardiac causes of dyspnea ⁽¹³⁾. Elevated BNP levels may lend weight to a suspected diagnosis of HF or trigger consideration of HF when the diagnosis is unknown but should not be used in isolation to confirm or exclude the presence of HF ^(17,20).

B. Ongoing Evaluation of Patients
1. Assessment of Volume Status
It is critically important for healthcare providers to evaluate the fluid or volume status of patients with HF during the initial visit and each follow-up examination. This assessment plays a pivotal role in determining the need for diuretic therapy and in detecting sodium excesses or deficiencies that may limit efficacy and decrease the tolerability of drugs used to treat HF. The physical examination is the primary step in evaluating the presence and severity of fluid retention in patients with HF. At each visit, healthcare providers should record the patient’s body weight and sitting and standing blood pressures and determine the degree of jugular venous distension and its response to abdominal pressure, the presence and severity of organ congestion (pulmonary rales and hepatomegaly), and the magnitude of peripheral edema in the legs, abdomen, presacral area, and scrotum, as well as ascites in the abdomen.

2. Laboratory Assessment
Serum electrolytes and renal function should be monitored routinely in patients with HF. Of particular importance is the serial measurement of serum potassium concentration, because hypokalemia is a common adverse effect of treatment with diuretics and may cause fatal arrhythmias and increase the risk of digitalis toxicity, whereas hyperkalemia may complicate therapy with angiotensin converting enzyme (ACE) inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and aldosterone antagonists. Worsening renal function may require adjustment of the doses of diuretics, renin-angiotensin-aldosterone system antagonists, digoxin, and noncardiac medications. Development of hyponatremia or anemia may be a sign of disease progression and is associated with impaired survival.

Serum BNP levels have been shown to parallel the clinical severity of HF as assessed by NYHA class in broad populations. Levels are higher in hospitalized patients and tend to decrease during aggressive therapy for decompensation (see Section 3.1.3.2 on BNP in the full-text guidelines) ⁽¹⁵⁾. However, it cannot be assumed that BNP levels can be used effectively as targets for adjustment of therapy in individual patients. Ongoing trials will help to determine the role of serial BNP measurements in both diagnosis and management of HF.

Repeat assessment of EF may be most useful when the patient has demonstrated a major change in clinical status. Both improvement and deterioration may have important implications for future care, although the recommended medical regimen should be continued in most cases. Improvement may reflect recovery from a previous condition, such as viral myocarditis or hypothyroidism, or may occur after titration of recommended therapies for chronic HF. Deterioration may reflect gradual disease progression or a new event, such as recurrent MI. Routine assessment of EF at frequent, regular, or arbitrary intervals is not recommended.

3. Assessment of Prognosis
Although both healthcare providers and patients may be interested in defining the prognosis of an individual patient with HF, the likelihood of survival can be determined reliably only in populations and not in individuals. However, some attempt at prognostication in HF may provide better information for patients and their families to appropriately plan for their futures. It also identifies patients in whom cardiac transplantation or mechanical device therapy should be considered.

	IV. Therapy

Top Table of Contents I. Introduction II. Characterization of HF... III. Initial and Serial... IV. Therapy V. Treatment of Special... VI. Patients With HF... VII. End-of Life Considerations VIII. Implementation of Practice... References

 
Table 2 describes cardiovascular medications useful for treatment of various stages of HF (see the Figure for an explanation of the stages of HF).

View this table: [in this window] [in a new window]   TABLE 2. Cardiovascular Medications Useful for Treatment of Various Stages* of Heart Failure

A. Patients at High Risk for Developing HF (Stage A)
Recommendations Class I

1. In patients at high risk for developing HF, systolic and diastolic hypertension should be controlled in accordance with contemporary guidelines. (Level of Evidence: A)
   
2. In patients at high risk for developing HF, lipid disorders should be treated in accordance with contemporary guidelines. (Level of Evidence: A)
   
3. For patients with diabetes mellitus (who are all at high risk for developing HF), blood sugar should be controlled in accordance with contemporary guidelines. (Level of Evidence: C)
   
4. Patients at high risk for developing HF should be counseled to avoid behaviors that may increase the risk of HF (e.g., smoking, excessive alcohol consumption, and illicit drug use). (Level of Evidence: C)
   
5. Ventricular rate should be controlled or sinus rhythm restored in patients with supraventricular tachyarrhythmias who are at high risk for developing HF. (Level of Evidence: B)
   
6. Thyroid disorders should be treated in accordance with contemporary guidelines in patients at high risk for developing HF. (Level of Evidence: C)
   
7. Healthcare providers should perform periodic evaluation for signs and symptoms of HF in patients at high risk for developing HF. (Level of Evidence: C)
   
8. In patients at high risk for developing HF who have known atherosclerotic vascular disease, healthcare providers should follow current guidelines for secondary prevention. (Level of Evidence: C)
   
9. Healthcare providers should perform a noninvasive evaluation of LV function (i.e., LVEF) in patients with a strong family history of cardiomyopathy or in those receiving cardiotoxic interventions. (Level of Evidence: C)
   

Class IIa

1. Angiotensin converting enzyme inhibitors can be useful to prevent HF in patients at high risk for developing HF who have a history of atherosclerotic vascular disease, diabetes mellitus, or hypertension with associated cardiovascular risk factors. (Level of Evidence: A)
   
2. Angiotensin II receptor blockers can be useful to prevent HF in patients at high risk for developing HF who have a history of atherosclerotic vascular disease, diabetes mellitus, or hypertension with associated cardiovascular risk factors. (Level of Evidence: C)
   

Class III

1. Routine use of nutritional supplements solely to prevent the development of structural heart disease should not be recommended for patients at high risk for developing HF. (Level of Evidence: C)
   

1. Control of Risk
a. Treatment of Hypertension
Elevated levels of diastolic and especially systolic blood pressure are major risk factors for the development of HF ^(21,22), and long-term treatment of both systolic and diastolic hypertension has been shown to reduce the risk of HF ^(23–25). A number of large, controlled studies have quite uniformly demonstrated that optimal blood pressure control decreases the risk of new HF by approximately 50% ⁽²⁶⁾.

Healthcare providers should lower both systolic and diastolic blood pressure in accordance with the recommendations provided in published guidelines, including the most recently published report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure ⁽²⁷⁾; target levels of blood pressure are lower in patients with associated major cardiovascular risk factors, especially those with diabetes mellitus ^(27a,27b). When an antihypertensive regimen is devised, optimal control of blood pressure should remain as the primary goal, with the choice of drugs determined by the concomitant medical problems (e.g., coronary artery disease, diabetes, or renal disease). Diuretic-based antihypertensive therapy has repeatedly been shown to prevent HF in a wide range of target populations ⁽³⁰⁾. Angiotensin converting enzyme inhibitors and beta-blockers are also effective in the prevention of HF ⁽²⁷⁾, whereas calcium antagonists and alpha-blockers are less effective in preventing HF syndrome ⁽³¹⁾. However, ACEIs and beta-blockers, as single therapies, are not superior to other antihypertensive drug classes in the reduction of all cardiovascular outcomes. Nevertheless, among patients with diabetes or other cardiovascular complications ^(32,33), ACEIs have been most notable with respect to a reduction in the onset of HF and new-onset diabetes. Likewise, compared with placebo, the ARBs losartan ⁽³⁴⁾ and irbesartan ⁽³⁵⁾ significantly reduced the incidence of HF in patients with type 2 diabetes mellitus and nephropathy. Ultimately, an appropriate antihypertensive regimen frequently consists of several drugs used in combination. Although prevention of HF is the focus of these guidelines, overall cardiovascular preventative strategies have also been the subject of published guidelines ⁽³⁶⁾.

b. Treatment of Diabetes
Obesity and insulin resistance are important risk factors for the development of HF ^(28,37). The presence of clinical diabetes mellitus markedly increases the likelihood of HF in patients without structural heart disease ⁽²⁹⁾ and adversely affects the outcomes of patients with established HF ^(38,39). In a study of patients with type 2 diabetes mellitus more than 50 years of age who had urinary albumin greater than 20 mg per liter, 4% of patients developed HF over the study period, of whom 36% died ⁽⁴⁰⁾. The occurrence of HF represents a major and adverse prognostic turn in a diabetic patient’s life. There is a differential gender effect associated with this risk; diabetes mellitus only modestly increases the risk of HF for men, but it increases the relative risk of HF more than 3-fold among women ⁽²¹⁾. Healthcare providers should make every effort to control hyperglycemia, although such control has not yet been shown to reduce the subsequent risk of HF. In addition, ACEIs or ARBs can prevent the development of end-organ disease and the occurrence of clinical events in diabetic patients, even in those who do not have hypertension ^(32,41). Long-term treatment with several ACEIs or ARBs has been shown to decrease the risk of renal disease in diabetic patients ^(42,42a), and prolonged therapy with the ACEI ramipril has been shown to lower the likelihood of cardiovascular death, MI, and HF ⁽³²⁾. Likewise, the use of ARBs in patients with diabetes mellitus and hypertension or LVH has been shown to reduce the incidence of first hospitalization for HF, in addition to having other beneficial effects on renal function ^(34,35,43).

c. Management of the Metabolic Syndrome
The clustering of cardiovascular risk factors in individual patients, termed the metabolic syndrome or syndrome X, includes any 3 of the criteria of abdominal adiposity, hypertriglyceridemia, low high-density lipoprotein, hypertension, and fasting hyperglycemia. It is estimated that the prevalence of the metabolic syndrome in the United States exceeds 20% of individuals who are at least 20 years of age, and 40% of the population over 40 years of age ⁽⁴⁴⁾. A number of trials are currently in progress to determine the most effective intervention for patients with the metabolic syndrome.

d. Management of Atherosclerotic Disease
Patients with known atherosclerotic disease (e.g., of the coronary, cerebral, or peripheral blood vessels) are likely to develop HF, and healthcare providers should seek to control vascular risk factors in such patients according to recommended guidelines ⁽³⁶⁾. In one large-scale trial, long-term treatment with an ACEI decreased the risk of the primary end point of cardiovascular death, MI, and stroke in patients with established vascular disease who were without evidence of HF or reduced LVEF at the time of randomization, but the incidence of new HF was not a primary or secondary end point although it was improved ⁽³²⁾. Among patients with established coronary artery disease and no HF, another ACEI significantly reduced the incidence of death, MI or cardiac arrest ⁽³³⁾. A more recent large trial of ACEI versus placebo failed to show a reduction in the primary composite end point, although a post hoc analysis did show some reduction in HF hospitalization ^(44a). The committee, in reviewing the accruing data, decided to change the level of recommendation for the use of ACEI for Stage A patients from Class I in the 2001 document to Class IIa in this document. Treatment of hyperlipidemia (in accordance with published guidelines) has been shown to reduce the likelihood of death and of HF in patients with a history of MI ^{(45,45a,45b,45c)}.

e. Control of Conditions That May Cause Cardiac Injury
Many therapeutic and recreational agents can exert important cardiotoxic effects, and patients should be strongly advised about the hazards of smoking, as well as the use of alcohol, cocaine, amphetamines, and other illicit drugs. Several epidemiological studies have revealed no correlation between the amount of alcohol ingested and the subsequent development of HF; nevertheless, the Writing Committee strongly believed that any patient with a history of alcohol abuse or with current substantial routine alcohol consumption and new-onset HF without other obvious cause should be counseled to become abstinent. Many HF programs limit alcoholic beverage consumption to no more than 1 alcoholic beverage serving daily for all patients with LV dysfunction, regardless of cause ^(46,47). Use of ephedra, formerly a common ingredient in over-the-counter weight loss preparations, may contribute to the development of HF as well ⁽⁴⁸⁾.

f. Other Measures
There is no direct evidence that control of dietary sodium or participation in regular exercise can prevent the development of HF. However, in patients with hypertension or other vascular disease, these efforts may have other health benefits and may enhance a general sense of well-being.

2. Early Detection of Structural Abnormalities
Asymptomatic patients with ventricular dilatation and reduced LVEF carry substantially higher risk for subsequent morbidity and mortality than the general population. It would be desirable to construct cost-effective strategies to identify such patients in the interest of reducing their subsequent risk. Limited information is available to support the cost-effectiveness of broad population screening. Brain natriuretic peptide levels represent a potential tool for this purpose ⁽⁴⁹⁾. An analysis of the implications of elevated BNP has suggested that the screening of asymptomatic people over the age of 60 years with this blood test could yield cost-effective improvement in clinical outcomes across the population ⁽⁵⁰⁾.

B. Patients With Cardiac Structural Abnormalities or Remodeling Who Have Not Developed HF Symptoms (Stage B)
Recommendations Class I

1. All Class I recommendations for Stage A should apply to patients with cardiac structural abnormalities who have not developed HF. (Levels of Evidence: A, B, and C as appropriate)
   
2. Beta-blockers and ACEIs should be used in all patients with a recent or remote history of MI regardless of EF or presence of HF (see Table 2). (Level of Evidence: A)
   
3. Beta-blockers are indicated in all patients without a history of MI who have a reduced LVEF with no HF symptoms (see Table 2and text). (Level of Evidence: C)
   
4. Angiotensin converting enzyme inhibitors should be used in patients with a reduced EF and no symptoms of HF, even if they have not experienced MI. (Level of Evidence: A)
   
5. An ARB should be administered to post-MI patients without HF who are intolerant of ACE inhibitors and have a low LVEF. (Level of Evidence: B)
   
6. Patients who have not developed HF symptoms should be treated according to contemporary guidelines after an acute MI. (Level of Evidence: C)
   
7. Coronary revascularization should be recommended in appropriate patients without symptoms of HF in accordance with contemporary guidelines (see ACC/AHA Guidelines for the Management of Patients With Chronic Stable Angina). (Level of Evidence: A)
   
8. Valve replacement or repair should be recommended for patients with hemodynamically significant valvular stenosis or regurgitation and no symptoms of HF in accordance with contemporary guidelines. (Level of Evidence: B)
   

Class IIa

1. Angiotensin converting enzyme inhibitors or ARBs can be beneficial in patients with hypertension and LVH and no symptoms of HF. (Level of Evidence B)
   
2. Angiotensin II receptor blockers can be beneficial in patients with low EF and no symptoms of HF who are intolerant of ACEIs. (Level of Evidence: C)
   
3. Placement of an ICD is reasonable in patients with ischemic cardiomyopathy who are at least 40 days post-MI, have an LVEF of 30% or less, are NYHA functional class I on chronic optimal medical therapy, and have reasonable expectation of survival with a good functional status for more than 1 year. (Level of Evidence: B)
   

Class IIb

1. Placement of an implantable cardioverter-defibrillator might be considered in patients without HF who have nonischemic cardiomyopathy and an LVEF less than or equal to 30% who are in NYHA functional Class I with chronic optimal medical therapy and have a reasonable expectation of survival with good functional status for more than 1 year. (Level of Evidence: C)
   

Class III

1. Digoxin should not be used in patients with low EF, sinus rhythm, and no history of HF symptoms, because in this population, the risk of harm is not balanced by any known benefit. (Level of Evidence: C)
   
2. Use of nutritional supplements to treat structural heart disease or to prevent the development of symptoms of HF is not recommended. (Level of Evidence: C)
   
3. Calcium channel blockers with negative inotropic effects may be harmful in asymptomatic patients with low LVEF and no symptoms of HF after MI (see text in Stage C). (Level of Evidence: C)
   

1. Prevention of Cardiovascular Events
a. Patients With an Acute MI
For recommendations on the treatment of patients with MI, see the ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction ⁽⁹⁾.

b. Patients With Chronic Reduction of LVEF but No Symptoms
Long-term treatment with an ACEI has been shown to delay the onset of HF symptoms and decrease the combined risk of death and hospitalization for HF in asymptomatic patients with reduced LVEF, whether due to a remote ischemic injury or to a nonischemic cardiomyopathy ^(51,52). Although a recent trial investigated patients with low EF and HF at the time of MI, there are no studies that specifically address use of ARBs in asymptomatic patients with reduced LVEF. Given the results of studies in symptomatic patients with low EF, ARBs may be an appropriate alternative, particularly in patients who cannot tolerate an ACEI. Furthermore, although controlled clinical trials are lacking, the use of beta-blockers in patients with a low EF and no symptoms (especially those with coronary artery disease) is also recommended ^(53,54). In such cases, the same beta-blockers should be used that were employed in the large HF trials.

The use of ICD therapy in patients with chronic reduction of LVEF but no symptoms has been evaluated in one large trial including only patients with ischemic cardiomyopathy. The trials assessing ICD for primary prophylaxis in non-ischemic cardiomyopathy have not included functional class I patients, and the efficacy of ICDs in this population as a whole is unknown ^(54a). The trial involving patients with ischemic cardiomyopathy included a subset of asymptomatic patients post-MI with LVEF 30% or less, and there was demonstrated benefit of ICD placement (MADIT-II) in that subset. The findings potentially apply to large numbers of patients, and the number needed to treat to have benefit would be great. The writing committee struggled with this issue because guidelines are meant to summarize current science and not take into account economic issues or the societal impact of making a recommendation. However, the committee recognizes that economic impact and societal issues will clearly modulate how these recommendations are implemented.

In contrast, there are no data to recommend the use of digoxin in patients with asymptomatic reduction of LVEF, except in those with atrial fibrillation. Likewise, there are no data to recommend the routine use of calcium channel blockers in patients with asymptomatic reduction of LVEF, but they have not been shown to have adverse effects and may be helpful for concomitant conditions such as hypertension. However, the use of calcium channel blockers with negative inotropic effects is not recommended in asymptomatic patients with EF less than 40% after MI ⁽⁵⁵⁾.

C. Patients With Current or Prior Symptoms of HF (Stage C)
1. Patients With Reduced LVEF
Recommendations Class I

1. Measures listed as Class I recommendations for patients in stages A and B are also appropriate for patients in Stage C. (Levels of Evidence: A, B, and C as appropriate)
   
2. Diuretics and salt restriction are indicated in patients with current or prior symptoms of HF and reduced LVEF who have evidence of fluid retention (see Table 3). (Level of Evidence: C)
   
3. Angiotensin converting enzyme inhibitors are recommended for all patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated (see Table 2 and text). (Level of Evidence: A)
   
4. Beta-blockers (using 1 of the 3 proven to reduce mortality, ie. bisoprolol, carvedilol, and sustained release metoprolol succinate) are recommended for all stable patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated (see Table 2 and text). (Level of Evidence: A)
   
5. Angiotensin II receptor blockers approved for the treatment of HF (see Table 2) are recommended in patients with current or prior symptoms of HF and reduced LVEF who are ACEI intolerant (see text for information regarding patients with angioedema). (Level of Evidence: A)
   
6. Drugs known to adversely affect the clinical status of patients with current or prior symptoms of HF and reduced LVEF should be avoided or withdrawn whenever possible (e.g., nonsteroidal anti-inflammatory drugs, most antiarrhythmic drugs, and most calcium channel blocking drugs; see text). (Level of Evidence: B)
   
7. Exercise training is beneficial as an adjunctive approach to improve clinical status in ambulatory patients with current or prior symptoms of HF and reduced LVEF. (Level of Evidence: B)
   
8. An implantable cardioverter-defibrillator is recommended as secondary prevention to prolong survival in patients with current or prior symptoms of HF and reduced LVEF who have a history of cardiac arrest, ventricular fibrillation, or hemodynamically destabilizing ventricular tachycardia. (Level of Evidence: A)
   
9. Implantable cardioverter-defibrillator therapy is recommended for primary prevention to reduce total mortality by a reduction in sudden cardiac death in patients with ischemic heart disease who are at least 40 days post-MI, have an LVEF less than or equal to 30%, with NYHA functional class II or III symptoms while undergoing chronic optimal medical therapy, and have reasonable expectation of survival with a good functional status for more than 1 year. (Level of Evidence: A)
   
10. Implantable cardioverter-defibrillator therapy is recommended for primary prevention to reduce total mortality by a reduction in sudden cardiac death in patients with nonischemic cardiomyopathy who have an LVEF less than or equal to 30%, with NYHA functional class II or III symptoms while undergoing chronic optimal medical therapy, and have reasonable expectation of survival with a good functional status for more than 1 year. (Level of Evidence: B)
    
11. Patients with LVEF less than or equal to 35%, sinus rhythm, and NYHA functional class III or ambulatory class IV symptoms despite recommended, optimal medical therapy and who have cardiac dyssynchrony, which is currently defined as a QRS duration greater than 0.12 ms, should receive cardiac resynchronization therapy unless contraindicated. (Level of Evidence: A)
    
12. Addition of an aldosterone antagonist is reasonable in selected patients with moderately severe to severe symptoms of HF and reduced LVEF who can be carefully monitored for preserved renal function and normal potassium concentration. Creatinine should be less than or equal to 2.5 mg/dL in men or less than or equal to 2.0 mg/dL in women and potassium should be less than 5.0 mEq/l. (Under circumstances where monitoring for hyperkalemia or renal dysfunction is not anticipated to be feasible, the risks may outweigh the benefits of aldosterone antagonists.) (Level of Evidence: B)
    

View this table: [in this window] [in a new window]   TABLE 3. Oral Diuretics Recommended for Use in the Treatment of Fluid Retention in Chronic Heart Failure

Class IIa

1. Angiotensin II receptor blockers are reasonable to use as alternatives to ACEIs as first-line therapy for patients with mild to moderate HF and reduced LVEF, especially for patients already taking ARBs for other indications. (Level of Evidence: A)
   
2. Digitalis can be beneficial in patients with current or prior symptoms of HF and reduced LVEF to decrease hospitalizations for HF. (Level of Evidence: B)
   
3. The addition of a combination of hydralazine and a nitrate is reasonable for patients with reduced LVEF who are already taking an ACEI and beta-blocker for symptomatic HF and who have persistent symptoms. (Level of Evidence: A)
   
4. Placement of an implantable cardioverter-defibrillator is reasonable in patients with LVEF of 30% to 35% of any origin with NYHA functional class II or III symptoms who are taking chronic optimal medical therapy and who have reasonable expectation of survival with good functional status of more than 1 year. (Level of Evidence: B)
   

Class IIb

1. A combination of hydralazine and a nitrate might be reasonable in patients with current or prior symptoms of HF and reduced LVEF who cannot be given an ACEI or ARB because of drug intolerance, hypotension, or renal insufficiency. (Level of Evidence: C)
   
2. The addition of an ARB may be considered in persistently symptomatic patients with reduced LVEF who are already being treated with conventional therapy. (Level of Evidence: B)
   

Class III

1. Routine combined use of an ACEI, ARB, and aldosterone antagonist is not recommended for patients with current or prior symptoms of HF and reduced LVEF. (Level of Evidence: C)
   
2. Calcium channel blocking drugs are not indicated as routine treatment for HF in patients with current or prior symptoms of HF and reduced LVEF. (Level of Evidence: A)
   
3. Long-term use of an infusion of a positive inotropic drug may be harmful and is not recommended for patients with current or prior symptoms of HF and reduced LVEF, 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)
   
4. Use of nutritional supplements as treatment for HF is not indicated in patients with current or prior symptoms of HF and reduced LVEF. (Level of Evidence: C)
   
5. Hormonal therapies other than to replete deficiencies are not recommended and may be harmful to patients with current or prior symptoms of HF and reduced LVEF. (Level of Evidence: C)
   

a. General Measures
Additions were made to the 3 classes of drugs that can exacerbate the syndrome of HF and that should be avoided in most patients:

1. Antiarrhythmic agents: Only amiodarone and dofetilide have been shown not to adversely affect survival ⁽⁵⁶⁾.
   
2. Calcium channel blockers: Only the vasoselective ones have been shown not to adversely affect survival ^(57,58).
   
3. Nonsteroidal anti-inflammatory drugs: A discussion of the use of aspirin as a unique agent is found later in this section.
   

Patients with HF should be monitored carefully for changes in serum potassium, and every effort should be made to prevent the occurrence of either hypokalemia or hyperkalemia. Many experts believe that serum potassium concentrations should be targeted in the 4.0 to 5.0 mmol per liter range.

b. Drugs Recommended for Routine Use
Diuretics
Thiazide diuretics may be preferred in hypertensive HF patients with mild fluid retention because they confer more persistent antihypertensive effects. Tables 3 and 4 illustrate oral and intravenous diuretics recommended for use in the treatment of chronic HF.

View this table: [in this window] [in a new window]   TABLE 4. Intravenous Diuretic Medications Useful for the Treatment of Severe Heart Failure

Inhibitors of the Renin-Angiotensin-Aldosterone System
Inhibition of the renin-angiotensin-aldosterone system can take place at multiple sites: at the level of the enzyme that converts angiotensin I to angiotensin II (ACEIs), at the angiotensin receptor (ARBs), or at the receptor for aldosterone, which is under control of both the renin-angiotensin system and other systemic and local influences (aldosterone antagonists). ACEIs are the best studied class of agents in HF, with multiple mechanisms of benefit for both HF, coronary disease, and other atherosclerotic vascular disease, as well as diabetic nephropathy. During chronic therapy with ACEIs, the renin-angiotensin system demonstrates partial "escape" from inhibition with "normalization" of angiotensin levels, in part owing to alternative local pathways for production of angiotensin. This leaves the potential for benefit from additional therapy with ARBs and with the aldosterone antagonists.

Angiotensin-Converting Enzyme Inhibitors
Analysis of a large collective experience indicates that ACEIs can alleviate symptoms, improve clinical status, and enhance the overall sense of well-being of patients with HF ^(59–70). In addition, ACEIs can reduce the risk of death and the combined risk of death or hospitalization ^(59,60,70). These benefits of ACE inhibition were seen in patients with mild, moderate, or severe symptoms and in patients with or without coronary artery disease.

Practical Use of ACE Inhibitors: Selection of Patients
Angiotensin converting enzyme inhibitors should be prescribed to all patients with HF due to LV systolic dysfunction with reduced LVEF unless they have a contraindication to their use or have been shown to be unable to tolerate treatment with these drugs. Because of their favorable effects on survival, treatment with an ACEI should not be delayed until the patient is found to be resistant to treatment with other drugs. ACEIs are often preferred over the use of ARBs or direct-acting vasodilators ^(70,71) because of the greater experience and weight of evidence supporting their effectiveness.

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 ACEI 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. More importantly, clinicians should not delay the institution of beta-blockers in patients because of a failure to reach target ACEI doses.

Two retrospective reviews have reported no adverse effects of concomitant aspirin use with ACEIs on long-term survival ^(72,73). Given these retrospective results, many physicians believe the data justify prescribing aspirin and ACEIs together when there is an indication for use of aspirin. These large overviews are subject to varying interpretation. Other physicians would consider not combining aspirin with an ACEI because there are no data to indicate that it can reduce the risk of ischemic events in patients with HF ^(74,75), or they might consider the use of an alternative antiplatelet agent such as clopidogrel, which does not interact with ACEIs and which may have superior effects in preventing ischemic events ⁽⁷⁶⁾. However, clopidogrel does not have an indication for the primary prevention of ischemic events. There may be an important interaction between aspirin and ACEI