Inclusion Criteria:

• Advanced HFrEF defined as including ALL:
  • LVEF ≤ 35% documented during the preceding 12 months;
  • NYHA class IV symptomatology, defined as chronic dyspnea or fatigue at rest or on minimal exertion in the previous 3 months, or patients who require chronic inotropic therapy;
  • Minimum of 3 months GDMT for HF and/or intolerant to therapy.
• Systolic blood pressure ≥ 90 mmHg.
• Serum NT-proBNP ≥ 800 pg/mL OR BNP ≥ 250 pg/mL (most recent - less than 3 months old).
• Any one or more of the following objective findings of advanced HF including:
  • Current inotropic therapy or use of inotropes in the past 6 months;
  • ≥ 1 hospitalization for heart failure in the past 6 months (not including the index hospitalization for inpatient participants);
  • LVEF ≤ 25% (within the past 12 months);
  • Peak VO2 < 55% predicted or peak VO2 ≤ 16 for men or ≤ 14 for women (Respiratory Exchange Ratio (RER) ≥ 1.05) (within the past 12 months);
  • 6 min walk test distance < 300 m (within the past 3 months).
• Age ≥ 18 years and ≤ 85 years.
• Signed Informed Consent form.

Exclusion Criteria:

• Currently taking Entresto™.
• History of hypersensitivity or intolerance (unmodifiable) to Entresto™, an ACEI or ARB as well as known or suspected contraindications (including hereditary angioedema) to the study drugs.
• Estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73 m2 at baseline.
• Co-morbid conditions that may interfere with completing the study protocol (e.g. recent history of drug or alcohol abuse) or cause death within 1 year.
• Symptomatic hypotension at randomization or systolic blood pressure < 90 mmHg.
• Serum potassium > 5.5 mmol/L.
• Severe liver dysfunction (Childs-Pugh Class C).
• Acute coronary syndrome within 4 weeks as defined by electrocardiographic (ECG) changes and biomarkers of myocardial necrosis (e.g. troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent).
• Planned or recent (≤ 4 weeks) PCI, coronary artery bypass grafting, or biventricular pacing.
• Currently hospitalized and listed status 1A, 1B or 1-4 for heart transplant.
• Current or scheduled for LVAD implantation within 30 days of study enrollment.
• Active infection (current use of oral or IV antimicrobial agents).
• Primary hypertrophic or infiltrative cardiomyopathy, acute myocarditis, constrictive pericarditis or tamponade.
• Complex congenital heart disease.
• Concomitant use of aliskiren in patients with diabetes or renal impairment (eGFR <60 mL/min/1.73 m²).
• Known pregnancy or anticipated pregnancy within the next 6 months or breastfeeding mothers.
• Enrollment in any other investigational clinical trial within 30 days prior to screening.
• Inability to comply with study procedures.