INTRODUCTION — Advanced heart failure (HF) occurs when patients with HF experience persistent severe symptoms that interfere with daily life despite maximum tolerated evidence-based medical therapy. Patients with advanced HF have alternatively been described as having "refractory," "end-stage," or "American College of Cardiology/American Heart Association stage D" HF [1,2]. (See "Determining the etiology and severity of heart failure or cardiomyopathy", section on 'Stages in the development of HF'.)
An overview of the clinical manifestations and diagnosis of advanced HF will be presented here. The management of advanced HF, diagnosis and management of patients with suspected HF, and management of acute decompensated HF will be discussed separately. (See "Management of refractory heart failure with reduced ejection fraction" and "Treatment of acute decompensated heart failure: Specific therapies" and "Treatment of acute decompensated heart failure: General considerations" and "Epidemiology of heart failure" and "Overview of the management of heart failure with reduced ejection fraction in adults".)
Symptoms and signs — While signs and symptoms of advanced HF are variable, common manifestations of advanced HF include exercise intolerance, unintentional weight loss, refractory volume overload, recurrent ventricular arrhythmias, as well as hypotension and signs of inadequate perfusion (eg, low pulse pressure). These signs and symptoms occur on optimal (maximum tolerated doses up to target) evidence-based medical therapy, following insertion of all appropriate devices (eg, cardiac synchronization therapy) and with all reversible causes of HF addressed.
Mortality risk increases with each subsequent HF hospitalization [3,4]. The presence of repeated hospitalizations, unplanned acute visits for HF decompensation, or complicated hospitalizations (eg, requiring intensive care unit care or inotropes) can suggest advanced HF .
Dyspnea, fatigue, and exercise intolerance — As HF progresses, patients frequently develop symptoms such as dyspnea, lightheadedness, or fatigue at rest or with minimal exertion that limits exercise capacity. Patients with advanced HF generally exhibit New York Heart Association (NYHA) functional class III (symptoms with minimal exertion) or IV (symptoms at rest or with any activity) symptoms (table 1). Since normal exercise capacity varies based on individual factors, such as age and activity level, standard benchmarks for exercise capacity may not be suitable for individual patients. Thus, a patient’s report of decline in exercise capacity over time can be most informative in signaling a significant change in exercise capacity. However, exercise limitation that is worrisome for advanced HF includes inability to walk a city block or perform activities of daily living such as bathing or dressing without limiting symptoms . Many patients will progress to have dyspnea at rest, including at night (orthopnea, paroxysmal nocturnal dyspnea). Poor functional status is an adverse prognostic indicator in patients with HF. (See "Predictors of survival in heart failure with reduced ejection fraction".)
The role of objective assessment of exercise tolerance is discussed below. (See 'Exercise testing' below.)
Unintentional weight loss — Unintentional weight loss sometimes leading to cachexia is a common complication of advanced HF. It is characterized by body wasting, including loss of lean tissue (ie, muscle) and fat . While often accompanied by anorexia (loss of appetite), it can occur despite adequate caloric intake, due to catabolic/anabolic imbalances.
Refractory volume overload — Patients with advanced HF often present with refractory volume overload despite escalating doses of diuretics. Volume overload can manifest as pulmonary congestion, peripheral edema, ascites, and elevated jugular venous pressure. A requirement of very high doses of loop diuretics, such as furosemide ≥160 mg/day or equivalent, or frequent use of metolazone is common in advanced HF. Worsening renal function and inadequate diuresis despite escalating doses of diuretics is also frequently observed. Volume assessment in HF is discussed in more detail separately. (See "Heart failure: Clinical manifestations and diagnosis in adults" and "Examination of the jugular venous pulse".)
Hypotension and signs of inadequate perfusion — On physical examination, patients with low cardiac output may have signs of poor perfusion, including narrowed pulse pressure, cool extremities, hypotension, and mental status changes.
Although many patients with HF (particularly those with HF with reduced ejection fraction) have low blood pressure as a result of the combined effect of medical therapy and cardiac dysfunction, hypotension (systolic blood pressure <90 mmHg) accompanied by symptoms such as lightheadedness and/or signs of organ dysfunction (eg, worsening renal function) can be indicative of advanced HF. Low blood pressure has been associated with increased mortality in patients with HF [6-8]. In particular, intolerance or the need to cut back doses of neurohormonal antagonists such as angiotensin converting enzyme inhibitors and beta blockers due to symptomatic hypotension is suggestive of poor prognosis and advanced HF [9,10].
Initial tests — Initial laboratory testing that may reveal signs of advanced HF includes blood tests, a chest radiograph, and an electrocardiogram (ECG).
Blood tests — While there are a multitude of blood tests that have been associated with prognosis in HF, the following are the most common blood test findings in patients with advanced HF.
Poor or worsening renal function — Impaired renal function is defined by a reduction in glomerular filtration rate (GFR), which is most often estimated using serum creatinine concentration. A variety of factors can contribute to a reduction in GFR in patients with HF, including neurohormonal adaptations, reduced renal perfusion, increased renal venous pressure, and right ventricular dysfunction. Both lower GFR and higher blood urea nitrogen (BUN) have been associated with increased mortality in HF [7,11-13]. In addition, worsening renal function, as evidenced by increase in BUN or creatinine over time, is associated with worse prognosis [14,15]. Advanced HF is often characterized by worsening renal function, often in response to diuresis for refractory volume overload. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology".)
Hyponatremia — Advanced HF is a cause of hyponatremia. Hyponatremia is associated with worse outcomes in patients with HF. The prognostic significance, pathogenesis, and management of hyponatremia in HF are discussed in detail elsewhere. (See "Hyponatremia in patients with heart failure".)
Hypoalbuminemia — Hypoalbuminemia (serum albumin ≤3.4 mg/dL) is common in HF and associated with worse prognosis [16,17]. It results from a multitude of factors including decreased liver synthesis, increased vascular permeability, increased degradation, and renal and gastrointestinal loss .
Congestive hepatopathy — Right-sided HF (which often accompanies left-sided HF) can result in hepatic congestion, which is often suggested by abnormal liver biochemical tests. A mild elevation in serum bilirubin (total bilirubin <3 mg/dL) is most common, though serum aminotransferase levels are elevated in a subset of patients. Serum alkaline phosphatase is usually normal or only mildly elevated. Elevated total bilirubin is associated with increased risk of death in HF . (See "Congestive hepatopathy".)
Elevated serum natriuretic peptide levels — While persistent elevation in B-type natriuretic peptide (BNP) and/or N-terminal pro-BNP is usually present in patients with advanced HF, there is no specific value that indicates that a patient has advanced HF. (See "Natriuretic peptide measurement in heart failure".)
Chest radiograph — Advanced HF is often characterized by episodes of fluid retention, which may manifest as pulmonary edema, pleural effusions, and/or pulmonary vascular congestion on chest radiograph, although when HF has been chronic, the radiographic signs of pulmonary congestion may be absent or mild due to increased pulmonary lymphatic drainage.
Electrocardiogram — ECG abnormalities are common in patients with advanced HF (eg, Q waves, ST and T wave abnormalities in patients with prior myocardial infarction or with cardiomyopathy). However, there is no ECG finding that is specific for advanced HF. Increased frequency or new onset atrial (eg, atrial fibrillation) and ventricular (eg, ventricular tachycardia) arrhythmias can contribute to the development of advanced HF symptoms and should be assessed.
DIAGNOSIS AND EVALUATION — The approach to the patient with suspected advanced heart failure (HF) includes history, physical examination, and diagnostic tests to help confirm the severity of HF and rule out alternative causes of refractory symptoms.
When to suspect advanced heart failure — Advanced HF should be suspected when a patient with HF experiences persistent severe symptoms despite optimal evidence-based therapy (pharmacologic therapy plus cardiac resynchronization therapy, as indicated and tolerated). The vast majority of patients presenting with advanced HF will have a known diagnosis of HF. Over time, many will progress to advanced HF that is refractory to guideline-directed medical therapy.
Less commonly, a patient may present with symptoms and signs of advanced HF without prior diagnosis of HF. In such cases, the patient should undergo initial stabilization followed by appropriately titrated evidence-based management (particularly for HF with reduced ejection fraction). The diagnosis of advanced HF is not made unless severe symptoms persist on maximally tolerated doses of evidence-based therapy, including cardiac resynchronization therapy (as indicated), with adequate time allowed for a therapeutic response. (See "Treatment and prognosis of heart failure with preserved ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults" and "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Pharmacologic therapy'.)
Approach to diagnosis and evaluation — We suggest the following approach to diagnosis and evaluation of advanced HF:
●History and physical examination to evaluate for symptoms and signs of advanced HF. (See 'Symptoms and signs' above.)
●Initial laboratory tests include:
•Blood tests including serum electrolytes (particularly serum sodium), complete blood count (CBC), renal function (eg, blood urea nitrogen and serum creatinine), thyroid function tests, serum albumin, liver function tests (serum bilirubin and serum aminotransferase levels), and serum brain natriuretic peptide (BNP) or NT-proBNP level. (See 'Blood tests' above and 'Evaluation for reversible causes and contributing factors' below.)
•A chest radiograph is commonly obtained in patients with dyspnea to assess for pulmonary edema and exclude other potential causes of dyspnea. (See 'Chest radiograph' above.)
•An electrocardiogram may be helpful to identify a factor contributing to the development of advanced HF such as atrial or ventricular arrhythmia.
●A complete transthoracic echocardiogram should be performed in all patients suspected of having advanced HF to evaluate for serial changes in biventricular and valvular function that may be contributing to worsening symptoms. (See 'Echocardiography' below.)
●Exercise testing consisting of a six-minute walk test and/or a cardiopulmonary exercise test should be performed in all patients suspected of having advanced HF that are able to ambulate and have no other contraindications to testing. (See 'Exercise testing' below.)
●A right heart catheterization is required in patients with advanced HF undergoing evaluation for mechanical circulatory support and cardiac transplantation. It can also be helpful to confirm the diagnosis of advanced HF. (See 'Right heart catheterization' below.)
How to diagnose advanced heart failure — A diagnosis of advanced HF is made based upon clinical evaluation confirming severe symptoms, episodes of refractory fluid retention and/or hypoperfusion, evidence of severe cardiac dysfunction (on echocardiogram or right heart catheterization), and evidence of severe impairment of functional capacity.
As there is no one single criterion for advanced HF that exists, the diagnosis is made based on clinical judgment after compiling data from the clinical examination and diagnostic testing. We recommend referral to an HF cardiologist when advanced HF is suspected, particularly if the patient may be a candidate for advanced HF therapies such as mechanical circulatory support or cardiac transplantation. We recommend use of the following criteria for diagnosis of advanced HF that are modified from the diagnostic criteria suggested by the European Society of Cardiology .
Advanced HF is present when the following criteria are met despite optimum medical management:
●Clinical evaluation confirms the presence of both of the following:
•Severe symptoms due to HF (NYHA functional class III or IV). (See 'Dyspnea, fatigue, and exercise intolerance' above.)
•Episodes of refractory fluid retention despite intravenous diuretics, hypoperfusion requiring intravenous inotropes or vasoactive agents, and/or recurrent malignant ventricular arrhythmias. Hypoperfusion may be diagnosed based on physical examination and/or laboratory testing (eg, signs of worsening renal function). (See 'Refractory volume overload' above and 'Hypotension and signs of inadequate perfusion' above.)
●AND diagnostic testing reveals both of the following:
•Objective evidence of severe cardiac dysfunction on echocardiogram and/or right heart catheterization, including one or more of the following:
-Left ventricular ejection fraction (≤30 percent). (See 'Echocardiography' below and "Tests to evaluate left ventricular systolic function".)
-LV diastolic dysfunction (eg, with pseudonormal or restrictive mitral inflow pattern) with left atrial dilation and/or pulmonary hypertension. (See "Echocardiographic evaluation of left ventricular diastolic function in adults".)
-Right ventricular dysfunction. (See "Echocardiographic assessment of the right heart".)
-Nonoperable severe valvular or congenital abnormalities.
-Low cardiac index (≤2.2 L/min/m2). (See 'Right heart catheterization' below.)
-High cardiac filling pressures (eg, mean pulmonary capillary wedge pressure >20 mmHg and/or right atrial pressure ≥12 mmHg). (See 'Right heart catheterization' below.)
•Severe impairment of exercise capacity, including one or more of the following:
-Six-minute walk test distance ≤300 m.
-Peak VO2 ≤12 kg/min or ≤50 percent predicted for age and sex. (See "Cardiopulmonary exercise testing in cardiovascular disease".)
-Inability to exercise due to HF.
Key tests — Tests that are helpful to confirm advanced HF include transthoracic echocardiography, exercise testing, and right heart catheterization.
Echocardiography — Echocardiography can be useful for assessment of biventricular function, estimating hemodynamics, and evaluation other cardiac conditions such as valve disease, congenital abnormalities, and pericardial disease. While advanced HF can occur in patients with HF and both preserved and reduced left ventricular ejection fraction, a drop in ejection fraction  or very low ejection fraction (≤25 to 30 percent)  has been associated with worse prognosis. Right ventricular dysfunction is associated with adverse prognosis in patients with HF, regardless of ejection fraction, and should be thoroughly assessed [22-24]. Echocardiography can also provide a noninvasive assessment of hemodynamics that can be helpful in patients with suspected or confirmed advanced HF. Variables such as cardiac output, right atrial pressure, pulmonary capillary wedge pressure, and pulmonary artery systolic pressure can be estimated using Doppler echocardiography and have been shown to be reliable when assessed by experienced operators .
Exercise testing — Objective assessment of exercise capacity with a six-minute walk test and/or a cardiopulmonary exercise test can confirm the presence of severely limited exercise capacity. A cardiopulmonary exercise test can further determine whether exercise limitation is due to cardiovascular factors.
Exercise capacity can be quantified by measuring oxygen uptake (VO2) and other parameters during a cardiopulmonary exercise test. The peak VO2 provides the most objective assessment of functional capacity in patients with HF, and lower values are associated with worse prognosis. A peak VO2 of ≤12 mL/kg/min (or ≤50 percent of age- and sex-predicted VO2) is used as a criterion for listing for cardiac transplantation . The six-minute walk test measures the distance ambulated on a level surface during six minutes, and shorter distances achieved are consistent with more severe HF. A distance of ≤300 m has been associated with increased risk of death  and correlates with peak VO2 in some populations . However, results are generally less informative than cardiopulmonary exercise testing, and cardiopulmonary exercise testing is favored if available, as it allows assessment of the contribution of cardiac versus noncardiac factors that can limit exercise. Exercise testing in HF is described in more detail elsewhere. (See "Exercise capacity and VO2 in heart failure" and "Heart transplantation in adults: Indications and contraindications".)
Right heart catheterization — Right heart (eg, pulmonary artery) catheterization can be helpful to measure intracardiac pressures and determine eligibility for advanced HF therapies. Abnormal hemodynamics are generally necessary for the diagnosis, although the precise pattern and severity of hemodynamic dysfunction may vary greatly from patient to patient, and abnormal hemodynamics, per se, are not sufficient for the diagnosis of advanced HF. Typically, there is persistently elevated left- and right-sided filling pressures (pulmonary capillary wedge pressure >20 mmHg, right atrial pressure ≥12 mmHg) and/or decreased cardiac index (≤2.2 L/min/m2) despite optimal medical therapy is concerning for advanced HF. Right heart catheterization is most informative when performed after volume status has been optimized. Pulmonary artery catheterization is discussed in more detail elsewhere. (See "Cardiac catheterization techniques: Normal hemodynamics" and "Pulmonary artery catheterization: Interpretation of hemodynamic values and waveforms in adults" and "Pulmonary artery catheterization: Indications, contraindications, and complications in adults".)
Evaluation for reversible causes and contributing factors — In patients diagnosed with advanced HF, it is important to perform a thorough evaluation to ensure that there are no potentially reversible etiologies or comorbidities causing or contributing to the patient’s signs and symptoms of advanced HF.
Potential reversible causes of advanced HF include severe coronary artery disease, severe operable valve stenosis or regurgitation, pericardial disease (eg, constrictive pericarditis), and a reversible cardiomyopathy (eg, stress or takotsubo cardiomyopathy). The evaluation of the etiology of HF is discussed separately. (See "Determining the etiology and severity of heart failure or cardiomyopathy".)
Contributing factors include severe anemia, thyroid disease, and sleep apnea.
●Severe anemia (hemoglobin <8 mg/dL) can result in impaired oxygen delivery to tissues and may contribute to symptoms such as dyspnea and fatigue in patients with suspected advanced HF. Treatment of the anemia may improve symptoms. Treatment options including blood transfusion, erythropoietin-stimulating agents, and iron supplementation are discussed in detail elsewhere. (See "Evaluation and management of anemia and iron deficiency in adults with heart failure".)
●Hyperthyroidism or hypothyroidism, per se, can lead to severe HF or contribute to the severity of HF due to other common causes . Therefore, thyroid function should be assessed and corrected before classifying HF as advanced. The cardiovascular effects of thyroid disorders are discussed in detail elsewhere. (See "Overview of the clinical manifestations of hyperthyroidism in adults", section on 'Cardiovascular'.)
●Sleep-disordered breathing (obstructive sleep apnea [OSA] and/or central sleep apnea with Cheyne-Stoke breathing [CSA-CSB]) is common in patients with HF. Both OSA and CSA-CSB can impair systolic and diastolic cardiac function, and the presence of either in patients with HF is associated with worse prognosis. Evaluation of patients with HF should include questions about potential sleep-disordered breathing symptoms (eg, snoring, excessive daytime somnolence, or poor sleep quality). (See "Sleep-disordered breathing in heart failure".)
DIFFERENTIAL DIAGNOSIS — When a diagnosis of advanced HF is suspected, it is important to exclude other potential causes of persistent severe symptoms and signs of HF despite optimum evidence-based therapy. Two key considerations are inadequate therapy for HF and presence of one or more concurrent conditions (eg, lung disease) in a patient with HF (that is not advanced) that may cause signs and symptoms like those of advanced heart failure.
In addition, reversible causes and contributing factors to HF should be excluded. (See 'Evaluation for reversible causes and contributing factors' above.)
Inadequate therapy — Poor adherence to medications and dietary restrictions (such as salt or fluid restriction) or undertreatment can contribute to persistent or worsening HF symptoms and should be assessed. Before assigning a patient a diagnosis of advanced HF, it is important to thoroughly review the patient’s current and prior HF therapies to ensure that all evidence-based therapies have been considered. Optimal medical management includes use of target doses (or maximally-tolerated doses when target doses are not tolerated) of evidence-based medications such as angiotensin converting enzyme (ACE) inhibitors and beta blockers. Furthermore, if one medication or medication class is not tolerated, alternative agents with similar therapeutic efficacy should have been tried. For example, if a patient does not tolerate ACE inhibitors due to cough, an angiotensin receptor blocker should be initiated as an alternative. Cardiac resynchronization therapy (CRT) should be added if indicated. It is also important to ensure that the patient has been given adequate time to respond to therapy (eg, one month after initiation of CRT). (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Pharmacologic therapy'.)
Concurrent conditions — In a patient with HF, the presence of one or more concurrent conditions affecting other organ systems (eg, kidney, lung, blood, thyroid, or liver) may cause symptoms and signs similar to those with advanced HF.
●Kidney disease – There are complex interactions between the heart and the kidney, such that worsening function in one organ impacts the performance of the other. In patients presenting with advanced HF symptoms and renal dysfunction, it is important to distinguish between underlying kidney disease and impaired kidney function due to cardiorenal syndrome. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on 'Diagnosis'.)
●Lung disease – Concomitant lung disease such as chronic obstructive pulmonary disease is common in patients with HF, present in up to 40 percent of patients [30-32]. Since lung disease and HF can both cause dyspnea, it can be challenging to sort out the relative contribution of each to symptom burden and functional status. Cardiopulmonary exercise testing can be helpful in distinguishing cardiac and pulmonary contributions to dyspnea in patients presenting with suspected advanced HF. Adequate treatment of lung disease may improve symptom burden in advanced HF. (See "Approach to the patient with dyspnea" and "Cardiopulmonary exercise testing in cardiovascular disease".)
●Liver disease – Cirrhosis can present with similar signs and symptoms as advanced HF, including ascites/abdominal distension, lower extremity edema, and fatigue. The presence of a normal jugular venous pressure on physical examination in a patient with ascites can be helpful in attributing the ascites to a noncardiac cause. However, it is important to recognize that longstanding right HF and elevated central venous pressure can also result in cirrhosis, and advanced HF and cirrhosis may coexist. (See "Congestive hepatopathy".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults".)
SUMMARY AND RECOMMENDATIONS
●When to suspect advanced heart failure – Advanced heart failure (HF) should be suspected when a patient with HF experiences persistent severe symptoms despite optimal evidence-based therapy (pharmacologic therapy plus cardiac resynchronization therapy, as indicated). The vast majority of patients presenting with advanced HF will have a known diagnosis of HF. A subgroup of patients with chronic HF will progress to develop advanced HF refractory to guideline-directed medical therapy. (See 'When to suspect advanced heart failure' above.)
●Symptoms and signs – While signs and symptoms of advanced HF are variable, common manifestations of advanced HF include dyspnea, fatigue, exercise intolerance, unintentional weight loss, refractory volume overload, hypotension, and signs of inadequate perfusion (diminished peripheral pulses or worsening renal function). (See 'Symptoms and signs' above.)
●Initial tests – The diagnostic evaluation of patients with suspected advanced HF includes a history, physical examination, blood tests, chest radiograph, electrocardiogram, transthoracic echocardiogram, and exercise testing. In addition, a right heart catheterization is required in patients with advanced HF who are undergoing evaluation for mechanical circulatory support and cardiac transplantation. (See 'Approach to diagnosis and evaluation' above.)
●How to diagnose advanced heart failure – A diagnosis of advanced HF is made based upon clinical evaluation confirming severe symptoms; episodes of refractory fluid retention, hypoperfusion, and/or recurrent malignant ventricular arrhythmias; evidence of severe cardiac dysfunction (on echocardiogram or right heart catheterization); and evidence of severe impairment of exercise capacity. (See 'How to diagnose advanced heart failure' above.)
●Evaluation for reversible causes and contributing factors – In patients diagnosed with advanced HF, it is important to perform a thorough evaluation to ensure that there are no potentially reversible etiologies causing or contributing to the patient’s signs and symptoms of advanced HF. Important contributing factors including anemia, thyroid disease, and sleep-disordered breathing. (See 'Evaluation for reversible causes and contributing factors' above.)
●Differential diagnosis – When a diagnosis of advanced HF is suspected, it is important to exclude other potential causes of persistent severe symptoms and signs of HF despite optimum evidence-based therapy. Two key considerations are inadequate therapy for HF and presence of one or more concurrent conditions (eg, lung disease) that may cause signs and symptoms like those of advanced HF. (See 'Differential diagnosis' above.)
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