Heart failure (HF) 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, fatigue, and fluid retention. The pathophysiology of HF (Fig. 1) is related to progressive activation of the neuroendocrine system to compensate for decreased effective circulating volume (Table 1), leading to total body volume overload and circulatory insufficiency.¹ These events culminate in the development of pulmonary congestion as well as peripheral edema. Specifically, the renin-angiotensin-aldosterone system (RAAS) is implicated; once activated, it can lead to volume expansion (sodium retention) and cardiac fibrosis (mediated through angiotensin II). Another recognized mechanism is disordered adrenergic stimulation as a key component of progression of disease. The term congestive heart failure (CHF) usually denotes a volume-overloaded status as a result of HF. Given that not all patients have volume overload at the time of the evaluation, congestive heart failure should be distinguished from the broader term heart failure.¹

• HF
• Congestive heart failure
• CHF
• Cardiac failure
• Cardiogenic shock
• Cardiogenic pulmonary edema

• There is variability in the reported demographics of HF due to heterogeneous definitions and classifications of HF. Incidence rate is lowest among White women and highest among Black men. African Americans have the highest risk for HF of the demographic groups with Blacks having a higher 5-yr mortality rate than Whites.¹
• The lifetime risk of developing HF is 20% for Americans ≥40 yr of age.
  1. In the U.S., HF incidence has largely remained stable over the past several decades, with >650,000 new HF cases diagnosed annually.²
  2. Based on NHANES data, from 2013 to 2016, an estimated 6.2 million Americans ≥20 yr of age had HF. This represents an increase from an estimated 5.7 million U.S. adults with HF from 2009 to 2012.⁵
  3. Projections show that the prevalence of HF will increase 46% from 2012 to 2030, resulting in >8 million people ≥18 yr of age with HF.⁶
  4. There has been an increase in the prevalence of HF in the population over time. This is primarily due to improved treatment of hypertension and valvular and coronary disease, allowing patients to survive an early death only to later develop HF.⁶
• HF is primarily a condition of the elderly. Approximately 80% of patients hospitalized with HF are older than 65 yr. HF is the most common inpatient diagnosis in the U.S. for patients aged >65 yr.⁶
• HF incidence increases with age, rising from approximately 20 per 1000 individuals 65 to 69 yr to >80 per 1000 individuals among those >85 yr. Before age 75, the incidence of HF is higher in males, but both sexes are equally affected after this age cutoff.⁵
• In the U.S., 809,000 hospital discharges and 2.3 million emergency department visits/physician visits were associated with HF in 2016, which is a decline compared with 1.02 million hospital discharges in 2006.^5,6
• Prevalence: 6.2 million persons in the U.S. and an estimated 26 million persons worldwide. The prevalence of HF is rising, especially in the elderly, particularly due to aging of the population and improved survival from other conditions.⁵
• The estimated (direct and indirect) cost of HF in the U.S. was >$40 billion in 2012, with over half of these costs spent on hospitalizations. The mean cost of HF-related hospitalizations is $23,077 per patient and is higher when HF was a secondary rather than the primary diagnosis.⁵
• HFrEF and HFpEF each make up about half of the overall HF burden of hospitalized HF events, half are in patients with HFrEF and the other half in patients with HFpEF.⁷
• The presence of ADHF services as an important juncture in the progression of HF, indicative of a worsening clinical course with increased risk of mortality and rehospitalization. An average hospitalization length for HF in the United States ranges around 4 to 5 days but carries a 1-yr mortality rate of ∼30%, over threefold of an increase from chronic, stable HF that does not require hospitalization.^8,9

The clinical and physical examination findings should be given the highest priority when determining the diagnosis of HF (Fig. 2). These signs and symptoms are dependent on the severity of disease, precipitant factors, comorbid conditions, and whether the HF symptoms are predominantly right-sided or left-sided. Clues in the patient’s history when evaluating HF are summarized in Table 4.

• Common clinical manifestations are:²
  1. Dyspnea on exertion, that can progress to dyspnea at rest, caused by increasing pulmonary vascular congestion
  2. Orthopnea, caused by increased venous return in the recumbent position and further elevated pulmonary venous pressure
  3. Paroxysmal nocturnal dyspnea (PND) resulting from multiple factors including increased venous return in the recumbent position, decreased Pao₂, and decreased adrenergic stimulation of myocardial function during sleep
  4. Nocturnal angina resulting from increased myocardial oxygen demand (secondary to increased venous return in the recumbent position causing increased preload) in patients with concomitant coronary artery disease (CAD)
  5. Cheyne-Stokes respiration (alternating phases of apnea and hyperventilation) caused by prolonged circulation time from lungs to brain as a result of impaired cardiac output
  6. Fatigue, lethargy, and decreased functional capacity resulting from low cardiac output and hypoperfusion of peripheral tissues
  7. Lack of appetite and nausea, early satiety or a poor appetite
  8. Table 5 summarizes common presenting symptoms and signs of decompensated HF
• Physical examination (Table 6):²
  1. Fine pulmonary crackles, wheezes, tachypnea, hypoxia (due to elevated pulmonary pressures). Crackles may be absent in chronic and long-standing high pulmonary venous pressure because it allows for lymphatic drainage in the lungs to increase.
  2. Tachycardia and narrowed pulse pressure (due to increased sympathetic tone)
  3. S₃ gallop, paradoxic splitting of S₂, jugular venous distention, peripheral edema in dependent tissues, congestive hepatomegaly, ascites, and hepatojugular reflux (due to volume overload)
  4. Perioral and peripheral cyanosis, decreased capillary refill, pulsus alternans, and cool extremities (due to decreased cardiac output)
• Six common clinical presentations identified by European Society of Cardiology of Acute Heart Failure Syndromes:¹⁰
  1. ADHF presenting with hypertension (SBP >160): The hypertension leads to increased afterload causing pulmonary vascular congestion
  2. Worsening or decompensation of chronic HF
  3. Flash pulmonary edema
  4. Cardiogenic shock
  5. Acute coronary syndrome (ACS) and ADHF
  6. Isolated RV failure
• Each of these scenarios may require different therapies to effectively stabilize and treat the patient

TABLE 4 Using the Medical History to Assess the Heart Failure Patient

Symptoms Associated With Heart Failure Include:

Fatigue Shortness of breath at rest or during exercise Dyspnea Tachypnea Cough Diminished exercise capacity Orthopnea Paroxysmal nocturnal dyspnea Nocturia Weight gain/Weight loss Edema (of the extremities, scrotum, or elsewhere) Increasing abdominal girth or bloating Abdominal pain (particularly if confined to the right upper quadrant) Loss of appetite or early satiety Cheyne-Stokes respirations (often reported by the family rather than the patient) Somnolence or diminished mental acuity

Historical Information That Is Helpful in Determining if Symptoms Are Due to Heart Failure Include:

A past history of heart failure Cardiac disease (e.g., coronary artery, valvular or congenital disease, previous myocardial infarction) Risk factors for heart failure (e.g., diabetes, hypertension, obesity) Systemic illnesses that can involve the heart (e.g., amyloidosis, sarcoidosis, inherited neuromuscular diseases) Recent viral illness or history of HIV or Chagas disease Family history of heart failure or sudden cardiac death Environmental and/or medical exposure to cardiotoxic substances Substance abuse Noncardiac illnesses that could affect the heart indirectly (including high output states such as anemia, hyperthyroidism, arteriovenous fistulae)

From Libby P et al: Braunwald’s heart disease: a textbook of cardiovascular medicine, ed 12, Philadelphia, 2022, Elsevier.

Figure 2 Flow chart for the evaluation of patients with heart failure (HF).

The diagnosis of HF is made using a combination of clinical judgment and initial and subsequent testing. Following thorough history and physical examination together with initial diagnostic testing, imaging (such as with echocardiography [ECG]) may still be necessary in ambiguous cases to definitively identify or exclude the diagnosis.

(From Libby P et al: Braunwald’s heart disease, a textbook of cardiovascular medicine, ed 12, Philadelphia, 2022, Elsevier.)

Acute precipitants of HF decompensation include nonadherence with salt restriction or medications (most common cause), any acute systemic illness, infection, arrhythmias (e.g., atrial fibrillation), ischemia or infarction, uncontrolled hypertension, new medications (e.g., negative inotropic agents such as calcium channel blockers/antiarrhythmic agents), NSAIDs, renal dysfunction, toxins (e.g., ethanol and anthracyclines), surgery, or valvular catastrophe.¹⁰

• Chronic obstructive pulmonary disease, asthma
• Cirrhosis
• Nephrotic syndrome
• Venous insufficiency
• Pulmonary embolism
• Acute respiratory distress syndrome
• Pneumonia, flu, and COVID-19
• Heroin overdose

• ACC/AHAA guidelines for initial and serial evaluation of HF are summarized in Table E8.
• Blood work (to diagnose potentially reversible causes, identify comorbidities, and assess disease severity):²
  1. CBC (to evaluate for anemia, infections), urinalysis, blood urea nitrogen, creatinine, electrolytes (worsening hyponatremia is a marker of disease severity and is associated with higher mortality rates), liver enzymes (hepatic congestion), thyroid function (especially in the elderly or patients with comorbid atrial fibrillation or known thyroid disease).
  2. Fig. E3 illustrates the use of biomarkers in HF. B-type natriuretic peptide (BNP) is a cardiac neurohormone secreted from the ventricles in response to elevated LV end-diastolic pressure. While the sensitivity is low in asymptomatic patients, low BNP level has a negative predictive value up to 90% in symptomatic patients. An elevated BNP correlates with severity of disease and parallels closely morbidity and mortality outcome measures. N-terminal-pro-BNP (NT-pro-BNP) is the cleavage remnant of BNP. It has a longer half-life and is renally cleared, making it susceptible to alterations in renal function. A level of <300 pg/ml has an age-independent 98% negative predictive value. There are new data to suggest that BNP screening and early intervention with risk factor modification in patients at risk of developing HF may prevent development of left ventricular dysfunction (class IIa recommendation). Natriuretic peptide biomarkers are also useful (class IA recommendation) both for diagnosis in patients presenting with dyspnea and for prognosis in patients with acute decompensated HF and chronic HF. Measurement of baseline levels of natriuretic peptide biomarkers on admission to the hospital is useful to establish a prognosis in acutely decompensated HF, and predischarge natriuretic peptide level can be useful to establish a postdischarge prognosis. There are insufficient data to recommend natriuretic peptide biomarker-guided therapy or serial measurements for the purpose of reducing hospitalization or deaths. ACC/AHA/HFSA guidelines for the use of biomarkers in HF are summarized in Table 9.
  3. Cardiac biomarkers may be elevated if ischemia is the precipitant factor. However, slight elevations are very common and may not always be due to obstructive coronary artery disease. These elevations could be due to subendocardial ischemia (due to increased end-diastolic pressure resulting in decreased perfusion leading to oxygen supply-demand mismatch) and necrosis, or cardiomyocyte damage from the inflammatory cytokines or oxidative stress. Impaired renal function is very common, and decreased clearance of the biomarkers can contribute to their elevation. Therefore these elevations should be interpreted in the context of the clinical setting. Despite that, in patients with ADHF, a positive cardiac troponin test (from whatever mechanism) is associated with worse prognosis.
  4. Screening for dyslipidemia and glucose intolerance, which are risk factors for CAD.
  5. If hemochromatosis is suspected (specifically in Northern European patients), consider checking a transferrin saturation and ferritin level.
  6. Consider HIV testing in high-risk patients and COVID-19 testing in all patients.
• ECG:²
  1. Look for signs of prior MI, chamber enlargement, hypertrophy, heart block, arrhythmia, and evidence of pericardial effusion.
  2. More than 25% of patients with HF have some form of intraventricular conduction abnormality that manifests as an increased QRS duration. The most common pattern seen is left bundle-branch block.
• Chest x-ray examination (Fig. 4):²
  1. Evaluate for pulmonary venous congestion, pulmonary edema, pleural effusion, cardiomegaly, chamber dilation, and Kerley B lines.
• Echocardiography:²
  1. Plays a critical diagnostic role in patients with HF and is useful in assessment of systolic, diastolic function in addition to assessment of valvular structure and function.
• Exercise stress testing:²
  1. May be useful in evaluating concomitant ischemic etiologies and assessment of degree of disability in stable compensated patients.
• Cardiac catheterization:²
  1. Left heart catheterization can help to identify coronary artery disease as a cause of HF. Right heart catheterization can help to evaluate intracardiac filling pressures, estimates of valvular areas, presence of intracardiac shunts, and calculation of hemodynamic properties such as cardiac output, systemic vascular resistance, and pulmonary artery wedge pressure to further guide management.
• Cardiac MRI:²
  1. Useful modality in accurately estimating EF (with less interstudy variability than conventional 2D echocardiography). MRI is also useful in excluding pericardial disease, identifying infiltrative disease, and assessing viability in cases of HF caused by underlying ischemic heart disease.

Figure E3 Indications for the use of biomarkers in heart failure.

*Other biomarkers of injury or fibrosis include soluble ST2 receptor, galectin-3, and high-sensitivity troponin. ACC, American College of Cardiology; AHA, American Heart Association; ADHF, acute decompensated heart failure; BNP, B-type natriuretic peptide; COR, class of recommendation; ED, emergency department; HF, heart failure; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; pts, patients.

(From Yancy CW et al: 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America, J Am Coll Cardiol 2017;70[6]:776.)

• Assess the etiology and severity of disease. Educate the patient and family about the nature of the disorder. Assess the home setting and if patient has social support to ensure compliance, especially for patients with dementia.
• Identify and correct precipitating factors (e.g., increased sodium load, medication noncompliance, ischemia, infections, anemia, thyrotoxicosis) and address lifestyle modification (e.g., smoking and alcohol cessation, weight reduction, avoiding use of NSAIDs). Anemia is common in patients with HF. In patients with NYHA class II and III symptoms and iron deficiency, intravenous (IV) iron replacement may be reasonable to improve functional status and quality of life (class IIb recommendation).^12,13 Treatments with erythropoiesis-stimulating agents (ESAs) have not shown improved clinical outcomes in patients with systolic HF and mild-to-moderate anemia and are thus not recommended.¹⁴ Table E10 describes ACC/AHA guidelines for treating patients at high risk for development of HF.
• Review list of medications and discontinue the ones that can contribute to HF (e.g., NSAIDs, antiarrhythmic drugs, calcium channel blockers, thiazolidinediones).²
• Dietary sodium restriction of <2 g/day is commonly recommended to patients with HF and is endorsed by many guidelines.²
• Restrict fluid intake to <2 L/day in patients with hyponatremia.²
• Caloric supplementation should be provided to patients with advanced HF with weight loss and muscle wasting due to cardiac cachexia. Weight loss may reflect cachexia caused by the higher total energy expenditure associated with HF compared with that of healthy sedentary subjects. The diagnosis of cardiac cachexia independently predicts a worse prognosis.¹⁰
• For patients with coexisting obstructive sleep apnea, continuous positive airway pressure (CPAP) may be reasonable after polysomnography (class IIb recommendation).²
• Exercise training (or regular physical activity) is recommended as safe and effective for patients with class I to III HF who are able to participate to improve functional status (class I recommendation). Cardiac rehabilitation is unfortunately an underused preventive measure, although it has been shown to reduce morbidity and mortality. Intensive cardiac rehabilitation can be useful in clinically stable patients with HF to improve functional capacity, exercise duration, health-related quality of life, and mortality (class IIa recommendation). Home-based cardiac rehabilitation is also an equally effective alternative if patients cannot participate in regular cardiac rehabilitation.²
• Pneumococcal vaccination, annual influenza vaccination.²
• ACC/AHA guidelines for treatment of asymptomatic left ventricular systolic dysfunction are summarized in Table E11.

• Four phases in treatment of ADHF:
  1. 1st phase: Initial stabilization and management (Table E12)
  2. 2nd phase: Inpatient hospital care (Table E13)
  3. 3rd phase: Early discharge planning and care
  4. 4th phase: Early postdischarge care
• 1st phase: Initial stabilization and management
  1. Short-term goals: Hemodynamic stabilization, stabilization of respiratory status, symptom relief, optimization of tissue perfusion, and recognition of more immediately life-threatening conditions (e.g., arrhythmias, valvular catastrophe, MI, cardiac tamponade). Initial therapy of ADHF is contingent on appropriate determination of clinical scenario.¹
  2. Management as per clinical scenario
     1. ADHF-associated hypertension: Goal is afterload reduction and decrease of systemic hypervolemia. Mode of treatment: Diuresis (IV loop diuretics) and vasodilators (acutely nitrates and morphine followed by treatment with ACE inhibitors or angiotensin receptor blockers [ARBs]).
     2. Worsening or decompensation of chronic HF (HFrEF or HFpEF): Goal is control of volume status. Treatment is accomplished with vasodilators and diuretics.¹⁰
     3. Flash pulmonary edema: Goal is afterload reduction (vasodilators such as nitrates acutely), respiratory status stabilization, and diuresis (IV loop diuretics). Rate control can be initiated in patients with atrial fibrillation or tachyarrhythmias as it may improve cardiac filling and function.¹⁰
     4. Cardiogenic shock: Goal is hemodynamic stabilization. Treatment consists of inotropes + vasopressors ± mechanical circulatory support ± emergent revascularization if indicated.¹⁰
     5. ACS and ADHF: Goal is hemodynamic stabilization + emergent restoration of coronary perfusion. See "Acute Coronary Syndrome."
     6. Isolated RV failure: Goals are identification of etiology: (1) Valvular, (2) pulmonary hypertension, and (3) primary RV failure secondary to ischemia. Treatment: Depends on etiology, either corrective surgery vs. treatment of pulmonary hypertension (endothelin antagonists, calcium channel blockers, phosphodiesterase inhibitors) vs. coronary reperfusion therapies.¹⁰

The goals of HF therapy are clinical improvement followed by stabilizing, slowing, or even reversing deterioration in myocardial function, and ultimately a reduction in risk of morbidity (including hospitalization rates) and mortality.²

• ACE inhibitors:¹⁸
  1. Reduce morbidity and mortality.
  2. Produce both venous and arterial vasodilation acutely, thereby reducing both preload and afterload.
  3. Potential mechanism of long-term benefit is attenuation of RAAS activation and decreased myocardial remodeling and fibrosis.
  4. Used as first-line therapy for asymptomatic LV dysfunction (LVEF <40%) and symptomatic systolic HF (ACC/AHA grades A to D).
  5. Therapy should be initiated at low doses to prevent hypotension and rapidly titrated to higher doses as tolerated.
  6. Contraindications to the use of ACE inhibitors are renal insufficiency (creatinine clearance <30 ml/min), bilateral renal artery stenosis, hyperkalemia, hypotension, or adverse reactions (e.g., angioedema).
• ARBs:¹⁹
  1. Receptor antagonists to the angiotensin II receptor.
  2. Clinical trials have not shown any superiority compared to ACE inhibitors in patients with systolic HF (LVEF <40%).
  3. Reserved for patients who are ACE inhibitor intolerant.
  4. Combination therapy with ARBs and ACE inhibitors is generally not recommended.
  5. Have a similar contraindication profile to ACE inhibitors. Routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is potentially harmful for patients with HFrEF.
• Angiotensin receptor-neprilysin inhibitor (ARNI) (valsartan/sacubitril):^20,21
  1. First-line therapy if affordable and side effects are tolerable.
  2. Neprilysin is an enzyme that degrades natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides.
  3. In a randomized controlled trial (PARADIGM-HF)²⁰ that compared valsartan/sacubitril with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either ACE inhibitor or ARB, the ARNI reduced the composite end point of cardiovascular death or HF hospitalization significantly, by 20%. Additionally, in another randomized controlled trial (PIONEER-HF),²¹ in HFrEF patients hospitalized with decompensated HF, initiation of valsartan/sacubitril caused a greater reduction in NT-proBNP concentration than enalapril. Rates of adverse effects did not significantly differ between the two groups.
  4. In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality (class I).
  5. ARNI should not be administered concomitantly with ACE inhibitors or within 36 h of the last dose of an ACE inhibitor (class III: Harm).
  6. ARNI should not be administered to patients with a history of angioedema (class III: Harm).
  7. ARNI has not shown additional benefit over ARB in patients with preserved ejection fraction and is not indicated in this group of patients.
• β-Adrenergic blockers (β-blockers):
  1. Reduce morbidity and mortality. Such benefits observed with bisoprolol (CIBIS II trial),²² metoprolol succinate (MERIT-HF trial),²³ and carvedilol (COPERNICUS trial).²⁴
  2. Benefit is believed to be conferred by blockade of sympathetic effects of neurohormonal stimulation due to HF.
  3. Are considered first-line therapy for symptomatic patients with systolic HF (NYHA class ≥II and LVEF <35%).
  4. Only carvedilol, bisoprolol, and metoprolol succinate (long acting) have been approved for the medical treatment of chronic HF; these agents are generally started in patients judged to be euvolemic and dosage is to be slowly up titrated as tolerated.
  5. Adverse effects include worsening HF (due to negative inotropic effects), fatigue, dizziness, bradycardia, hypotension, and bronchospasm.
• Aldosterone receptor antagonists:
  1. Reduce morbidity and mortality.
  2. Indicated in patients with NYHA class II-IV HF, with LVEF ≤35%, already treated with ACE inhibitors and β-blockers without significant renal insufficiency or hyperkalemia. Patients with NYHA class II should have a history of prior cardiovascular hospitalization or elevated plasma natriuretic peptide levels to be considered for aldosterone receptor antagonists. Creatinine should be ≤2.5 mg/dl in men or ≤2.0 mg/dl in women (or estimated glomerular filtration rate >30 ml/min/1.73 m²), and potassium should be <5.0 mEq/L. They are also indicated for post-MI patients with EF ≤40% who have either symptomatic HF or diabetes mellitus.
  3. Spironolactone may cause gynecomastia, galactorrhea, and hyperkalemia (especially in patients with baseline renal insufficiency or type 4 renal tubular acidosis). It has been best studied in chronic HF with NYHA class III to IV symptoms (RALES study).²⁵
  4. Eplerenone is associated with fewer endocrine side effects and has especially been studied in post myocardial infarction left ventricular dysfunction (EPHESUS trial)²⁶ and in chronic systolic HF with only class II symptoms (EMPHASIS-HF trial).²⁷
  5. Inappropriate use of aldosterone receptor antagonists is potentially harmful because of life-threatening hyperkalemia or renal insufficiency when serum creatinine is >2.5 mg/dl in men or >2.0 mg/dl in women (or estimated glomerular filtration rate <30 ml/min/1.73 m²), and/or potassium >5.0 mEq/L.
• Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor:
  1. SGLT2 inhibitors are known to lower blood sugar in patients with type 2 diabetes mellitus. However, they also possess properties associated with natriuresis, decreased fluid retention and edema, decreased RAAS activation, decreased sympathetic nervous system, reduced inflammation, and reduced oxidative stress. Thus, they are associated with improved cardiac structure and function (decreased preload, reduced remodeling/fibrosis, improved systolic function). They are also associated with improved endothelial function and overall improved vascular function.
  2. Currently used SGLT2 inhibitors include empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin.
  3. Dapagliflozin has been shown to reduce cardiovascular deaths and hospitalizations in patients with NYHA class II, III, or IV HF (LVEF ≤40%) regardless of the presence or absence of diabetes (DAPA-HF).²⁹
  4. Empagliflozin has been shown to reduce HF hospitalizations and cardiovascular deaths in patients with HF with both reduced ejection fraction (EMPEROR-Reduced)³⁰ and preserved ejection fraction (EMPEROR-Preserved).³¹
  5. According to the new HF guidelines, in patients with symptomatic chronic HFrEF (EF≤40%), SGLT2i are now recommended to reduce hospitalization for HF and cardiovascular mortality, irrespective of the presence of type 2 diabetes (class I recommendation).² In patients with HFrEF, the new guidelines support the combination use of ARNI, β-blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.
• Diuretics:³³
  1. They are used to maintain euvolemia and to improve symptoms as discussed previously.
  2. Although data on diuretic efficacy are limited, a meta-analysis of a few small trials found that they were associated with reduction in mortality as well as reduced hospitalization for HF.
  3. Of note, loop diuretics with better bioavailability, such as torsemide and bumetanide, may be used in diuretic-resistant patients but are generally more expensive.
  4. The ADVOR trial³⁴ revealed that the addition of acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium, to loop diuretics can improve the efficiency of loop diuretics and lead to faster decongestion in patients with acute decompensated HF with volume overload.
• Combination of isosorbide dinitrate and hydralazine:³⁵
  1. Cause venous (nitrates) and arteriolar (hydralazine) vasodilation resulting in decreased preload and afterload.
  2. The combination of hydralazine and isosorbide dinitrate is recommended to reduce morbidity and mortality for patients self-described as African Americans with NYHA class III to IV HFrEF receiving optimal therapy with ACE inhibitors and β-blockers, unless contraindicated.
  3. A combination of hydralazine and isosorbide dinitrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated.
  4. Adverse effects of nitrates include hypotension, headaches, and tolerance as well as reflex tachycardia and lupus-like syndrome with hydralazine.
• Digoxin:³⁶
  1. Positive inotropic and negative chronotropic drug that works by inhibition of the sodium-potassium transmembrane exchange pump and through its vagomimetic action.
  2. Commonly used in patients with concomitant atrial fibrillation.
  3. Has been shown to reduce HF-related hospitalizations but does not confer any mortality benefit (DIG trial).³⁶ However, there is evidence suggesting that digoxin may actually have an effect on survival that varies with the serum digoxin level; survival was improved when the level was between 0.5 and 0.8 ng/ml (most often in men) and significantly worsened when it was ≥1.2 ng/ml and >0.9 mg/ml in women.
  4. Caution must be used in patients with abnormal renal function to avoid digoxin toxicity and life-threatening arrhythmia. Avoid hypokalemia because potassium competes with digoxin on the same site of the Na⁺-K⁺-ATPase pump.
• I_f channel inhibitor (ivabradine):³⁷
  1. Ivabradine is a new therapeutic agent that selectively inhibits the I_f current in the sinoatrial node, providing heart rate reduction.
  2. Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who are receiving guideline-directed therapy, including a β-blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest (class IIa).
• Cardiac resynchronization therapy (CRT):³⁸
  1. Improves morbidity and mortality rates in selected patients.
  2. The presence of a bundle-branch block or other intraventricular conduction delay (IVCD) can cause ventricular dyssynchrony, which induces regional loading disparities and reduces the efficiency of ventricular contraction, thereby further impairing the systolic function of a failing ventricle.
  3. CRT is indicated for patients who have LVEF ≤35%, sinus rhythm, left bundle-branch block with a QRS duration of 150 ms or greater, and NYHA class II, III, or ambulatory IV symptoms on guideline-directed medical therapy. CRT is NOT indicated in patients whose functional status and life expectancy are limited predominantly by chronic noncardiac conditions. Life expectancy should be >1 yr.
  4. In the appropriate subset of patients, CRT in addition to optimal medical therapy has been shown in numerous clinical trials to improve symptoms by at least one NYHA class, improve 6-min walk distance and quality of life, reduce rate of HF-related hospitalization, and reduce rate of all-cause and cardiovascular mortality.
  5. ACC/AHA guidelines for cardiac resynchronization therapy are summarized in Table E18.
• Implantable cardioverter-defibrillators (ICDs):^2,39
  1. Sudden cardiac death (SCD) is a common cause of death in patients with HF in both ischemic and nonischemic cardiomyopathies. Ventricular tachycardia (VT) degenerating into ventricular fibrillation (VF) is the culprit in the majority of patients with SCD, although bradyarrhythmias do also occur with less frequency.
  2. ICD therapy is recommended for primary prevention of SCD to reduce total mortality in selected patients with nonischemic dilated cardiomyopathy or ischemic heart disease at least 40 days post-MI with LVEF ≤35% and NYHA class II or III symptoms on chronic guideline-directed medical therapy, who have reasonable expectation of meaningful survival for >1 yr.
  3. Patients with HF who survive an episode of sudden cardiac arrest or experience sustained VT in the presence of LVEF <35% are at high risk for future arrhythmic events and SCD and obtain a mortality benefit from ICD placement for secondary prevention, with or without adjunctive therapies such as antiarrhythmic drugs, radiofrequency ablation, surgery, or transplant.
  4. ACC/AHA guidelines for indications for implantable cardioverter-defibrillators are summarized in Table E19.
• In the absence of an indication (e.g., atrial fibrillation), routine use of anticoagulation is currently not recommended in patients with HF. Even with the increased risk for LV thrombus formation in dilated cardiomyopathy and subsequent thromboembolization, data are conflicting about benefits of antithrombotic (antiplatelet or anticoagulant) therapy for primary prevention to reduce thromboembolic events or mortality in patients with systolic HF who are in sinus rhythm (SOLVD, V-HeFT, SAVE, HELAS, and WASH trials). It may be reasonable to consider anticoagulation for secondary prevention in patients with HF who had a prior thromboembolic event; however, risks and benefits should be carefully assessed.
• Antiplatelet agents are recommended for patients with concomitant CAD.
• Statins are not beneficial as adjunctive therapy when prescribed solely for the diagnosis of HF in the absence of other indications for their use.
• Calcium channel blocking drugs are not recommended as routine treatment for patients with HFrEF.
• Omega-3 polyunsaturated fatty acid supplementation is reasonable to use as adjunctive therapy in patients with NYHA class II to IV symptoms and HFrEF or HFpEF, unless contraindicated, to reduce mortality and cardiovascular hospitalizations.
• Percutaneous coronary intervention (PCI) or surgical revascularization should be considered in patients with HF and significant CAD who are revascularization candidates.
• In general, quadruple therapy, if tolerated, is recommended as foundational therapy. If all four therapies (ARNI, β-blocker, MRA, SGLT2 inhibitor) are initiated simultaneously at low doses, all pathways are blocked to some degree, and this results in rapid improvement of mortality and health status as well as rapid reduction of HF hospitalizations. Some therapies offer further incremental benefit with increased doses (particularly ARNI and β-blocker), so if a patient tolerates quadruple therapy, doses can be increased to maximally tolerated doses.
• The following drugs can be added in selected patients in the absence of contraindications:
  1. Aldosterone antagonists improve survival in NYHA class II with LVEF <30% or NYHA class III-IV with EF <35%. Kidney function should be stable with eGFR ≥30 ml/min and potassium <5 mEq/L.
  2. Combination of hydralazine with a nitrate in patients (particularly African Americans) with a reduced EF.
  3. Digoxin reduces hospitalizations for HF and controls HR in atrial fibrillation. It can also help control symptoms.

• To date, there is a relative dearth of clinical trials examining effective chronic treatment strategies in this subset of patients with HFpEF. Current therapies are mainly for symptomatic relief. ACC/AHA guidelines for treatment of patients with end-stage JF are summarized in Table E20.
• Therapy mainly centers on relief of volume overload with judicious diuretic use (Table 17), treatment of ischemia via coronary revascularization (Table E21), management of atrial fibrillation, controlling heart rate and blood pressure to prevent acute decompensation, and restriction of sodium and fluid to prevent volume overload.
• Recently, SGLT2 inhibitor has shown to reduce the combined risk of worsening HF or cardiovascular death among patients with HF and a mildly reduced or preserved ejection fraction.⁴⁰
• Diuretics should be used for relief of symptoms due to volume overload in patients with HFpEF.
• The use of β-blocking agents, ACE inhibitors, and ARBs in patients with hypertension is reasonable to control blood pressure in patients with HFpEF.
• The use of ARBs might be considered to decrease hospitalizations for patients with HFpEF.
• Aldosterone antagonists may be used in appropriate patients with HFpEF (EF >45%, elevated BNP or HF admission in the past year, potassium <5.0 mEq/L, estimated glomerular filtration rate >30 and creatinine <2.5 mg/dl) to decrease hospitalizations (class IIb recommendation).
• Routine use of nitrates or phosphodiesterase-5 inhibitors to increase activity or quality of life in patients with HFpEF is not recommended as there is no benefit.
• There is no evidence to support routine use of nutritional supplements, and they are not recommended for patients with HFpEF.
• Surgical options (Table E22) for contributing critical aortic stenosis, constrictive pericarditis, and hypertrophic cardiomyopathy (HCM) should be entertained in appropriate patients.
• In patients with comorbidities including anemia, hypertension, and sleep apnea, the following recommendations are made:
  1. IV iron replacement in patients with NYHA class II and III HF and iron deficiency (ferritin <100 ng/ml or 100 to 300 ng/ml with transferrin saturation <20%) to improve functional status and quality of life (class IIb recommendation).
  2. Titration of medical therapy to attain systolic blood pressure <130 mm Hg is recommended in patients with HFrEF and hypertension, as well as in patients with HFpEF and persistent hypertension after treatment of volume overload (class I recommendation).
  3. A formal sleep assessment should be obtained in patients with NYHA class II to IV HF with suspicion of sleep-disordered breathing. Continuous positive airway pressure should be used in patients with HF and obstructive sleep apnea to improve sleep quality and daytime sleepiness (class IIb recommendation).

• Coordination of care is essential in patients with chronic HF.
• Annual mortality of systolic HF ranges from 10% in stable patients with mild symptoms to 50% in patients with NYHA class IV disease (a mortality rate rivaling some malignancies). The Seattle Heart Failure Model provides an accurate estimate of 1-, 2-, and 3-yr survival before and after different therapies. This model can be useful to assess the need for LV assist device implantation or urgent transplantation. The calculator is available online at http://depts.washington.edu/shfm/.
• Cardiac transplantation has a 5-yr survival rate of ∼70% and represents a viable option in selected patients. Fig. E6 describes an algorithm for evaluation of potential heart transplant recipient.⁴¹
• The use of an LV assist device (LVAD) in patients with advanced HF can result in a clinically meaningful survival benefit and improve quality of life in patients who are not candidates for cardiac transplantation.^41,42 There are two approved uses of LVADs specifically as a bridge to transplant and as destination therapy. There are two major categories of LVAD pulsatile flow devices vs. continuous flow devices. Continuous flow devices are associated with increased survival as destination therapy as compared to medically managed controls (REMATCH trial).⁴⁰

Figure E6 Algorithm for evaluation of the potential heart transplant recipient.

BMI, Body mass index; FVC, forced vital capacity; FEV, forced expiratory volume; HIV, human immunodeficiency virus; VAD, ventricular assist device.

(From Zipes DP: Braunwald’s heart disease: a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.)

• Heart Failure (Patient Information)