What are the stepwise management strategies for Heart Failure with Reduced Ejection Fraction (HFrEF)?

From the Guidelines

Management of heart failure with reduced ejection fraction (HFrEF) should follow a stepwise approach, prioritizing guideline-directed medical therapy (GDMT) and device therapy to improve symptoms, quality of life, and survival, as recommended by the 2022 AHA/ACC/HFSA guideline 1 and further supported by the 2024 ESC guidelines for the management of chronic coronary syndromes 1.

Stepwise Approach to HFrEF Management

The management of HFrEF involves several key steps, including:

• Establishing the diagnosis of HFrEF and addressing congestion
• Initiating GDMT with four foundational medication classes: an angiotensin receptor-neprilysin inhibitor (ARNI) or an angiotensin-converting enzyme inhibitor (ACEI), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor
• Titrating medications to target doses as tolerated, with ongoing reassessment of symptoms, labs, health status, and left ventricular ejection fraction (LVEF)
• Considering additional therapies, such as diuretics, hydralazine plus isosorbide dinitrate, and device therapy, including implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT), for patients with persistent symptoms and EF ≤35%

Key Medications and Therapies

The following medications and therapies are recommended for the management of HFrEF:

• ARNI or ACEI: sacubitril/valsartan or lisinopril/enalapril, respectively
• Beta-blocker: carvedilol, metoprolol succinate, or bisoprolol
• MRA: spironolactone or eplerenone
• SGLT2 inhibitor: dapagliflozin or empagliflozin
• Diuretics: furosemide for volume management
• Hydralazine plus isosorbide dinitrate: especially beneficial in Black patients
• ICD: for primary prevention of sudden cardiac death in patients with EF ≤35% and NYHA class II-III
• CRT: for patients with EF ≤35%, sinus rhythm, and QRS duration ≥150 ms with left bundle branch block (LBBB) QRS morphology

Ongoing Management and Referral

Ongoing management of HFrEF involves:

• Serial reassessment of symptoms, labs, health status, and LVEF
• Optimization of GDMT and device therapy as needed
• Referral to a heart failure specialty care team for patients with advanced HFrEF or those requiring complex management
• Consideration of advanced therapies, such as left ventricular assist devices and heart transplantation, for patients with end-stage HFrEF.

From the FDA Drug Label

1.1 Adult Heart Failure Sacubitril and valsartan tablets are indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure and reduced ejection fraction.

In trials in patients treated with digitalis and diuretics, treatment with enalapril resulted in decreased systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure and heart size, and increased cardiac output and exercise tolerance.

The management of Heart Failure with reduced Ejection Fraction (HFrEF) involves a stepwise approach. The initial step typically involves the use of an Angiotensin-Converting Enzyme (ACE) inhibitor such as enalapril 2 to reduce systemic vascular resistance and improve cardiac output.

If the patient remains symptomatic, the next step may involve the addition of a beta-blocker (not mentioned in the provided drug labels) or the replacement of the ACE inhibitor with an Angiotensin Receptor-Neprilysin Inhibitor (ARNI) such as sacubitril and valsartan 3, which has been shown to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure and reduced ejection fraction.

The choice of medication and the order in which they are used may vary depending on the individual patient's condition and response to treatment. It is essential to carefully evaluate the patient's symptoms, medical history, and current medications before making any changes to their treatment plan.

From the Research

HFrEF Management Stepwise

• The management of Heart Failure with Reduced Ejection Fraction (HFrEF) involves a stepwise approach, starting with basic treatment strategies such as diuretics for symptom relief and quadruple therapy (Angiotensin receptor blocker/neprilysin inhibitors, evidence-based beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors) for reduction in hospitalizations, all-cause mortality, and cardiovascular mortality 4.
• Other medications such as intravenous iron, ivabradine, hydralazine/nitrates, and vericiguat may also have a role in certain subgroups of HFrEF patients 4.
• Specific groups of patients with HFrEF may also be candidates for various device therapies such as implanted cardioverter defibrillators, cardiac resynchronization therapy, and trans catheter mitral valve repair 4.

Initiation and Optimization of Therapy

• The initiation or optimization of the four pillars of HFrEF therapy (beta-blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium-glucose cotransporter-2 inhibitors) during hospitalization for acute decompensation is feasible and well-tolerated 5.
• Early intervention leads to improvements in clinical parameters and functional status, supporting guideline recommendations for in-hospital initiation or optimization of HFrEF therapy 5.
• Special consideration should be given to renal function when optimizing therapy, as patients with advanced renal failure have poor prognosis in the presence of HFrEF with limited treatment options 5, 6.

Challenges in Specific Patient Populations

• HFrEF is frequently accompanied by the presence of cardiac and non-cardiac comorbidities that may greatly influence the management and prognosis of the disease, such as atrial fibrillation, renal disease, and elderly patients 6.
• AF aggravates heart failure and contributes to HF-related adverse clinical outcomes, requiring special consideration in HFrEF management 6.
• The kidney function is largely affected by the reduced cardiac output developed in the setting of HFrEF, and the neurohormonal feedback effects create a complex interplay that poses challenges in the management of HFrEF when renal function is significantly impaired 6.

New Pharmacological Treatments

• New medications for treating chronic heart failure have been clinically applied, but there is controversy surrounding drug selection and whether patients with HFrEF benefit from these medications 7.
• A Bayesian network meta-analysis compared and ranked different new pharmacological treatments in patients with HFrEF, including ivabradine, levosimendan, omega-3, tolvaptan, recombinant human B-type natriuretic peptide, isosorbide dinitrate and hydralazine, and angiotensin-neprilysin inhibition 7.
• The analysis confirmed the effectiveness of the included new pharmacological treatments for optimizing the structural performance and improving the cardiac function in the management of patients with HFrEF 7.