What are the indications for Entresto (sacubitril/valsartan)?

Entresto (Sacubitril/Valsartan) Indications

Entresto is FDA-approved to reduce the risk of cardiovascular death and hospitalization in adult patients with chronic heart failure, with benefits most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal, and for treating symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. 1

FDA-Approved Indications

Adult Heart Failure

• Primary indication: Reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure 1
• Target population: Benefits are most clearly evident in patients with LVEF below normal (no specific ejection fraction cutoff specified in current labeling) 1
• Functional class: Typically used in NYHA class II-IV patients 2

Pediatric Heart Failure

• Indication: Treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older 1
• Expected benefit: Reduces NT-proBNP and is expected to improve cardiovascular outcomes 1

Guideline-Recommended Use in Heart Failure with Reduced Ejection Fraction (HFrEF)

Replacement Therapy for ACE Inhibitors/ARBs

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. 3, 4

• The 2022 AHA/ACC/HFSA guidelines give this a Class 1 recommendation based on the PARADIGM-HF trial, which demonstrated a 20% relative reduction in the composite endpoint of cardiovascular death or HF hospitalization compared to enalapril 4
• This benefit was consistent across prespecified subgroups and observed to a similar extent for both death and HF hospitalization 4

De Novo Initiation (Without Prior ACE Inhibitor/ARB)

Direct-to-ARNI initiation is now recommended and does not require pretreatment with an ACE inhibitor or ARB. 5

• Recent data from clinical studies demonstrate that directly initiating an ARNI is a safe and effective strategy 5
• In hospitalized patients: ARNI should be initiated de novo in patients hospitalized with acute HFrEF before discharge in the absence of contraindications, based on the PIONEER-HF trial showing reduction in NT-proBNP levels without increased adverse events 4
• In chronic HFrEF: ARNI may be initiated de novo in patients with chronic symptomatic HFrEF to simplify management, though data are more limited 4
• The PROVE-HF study demonstrated tolerability and significant reverse cardiac remodeling (average 12% increase in LVEF by 1 year) among those with de novo HFrEF or naive to ACEIs/ARBs 5

Patient Eligibility Criteria from PARADIGM-HF

Patients enrolled in the pivotal trial had: 3

• Mild-to-moderate HF characterized by either:
  • Mildly elevated natriuretic peptide levels (BNP >150 pg/mL or NT-proBNP ≥600 pg/mL), OR
  • BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL with a prior hospitalization in the preceding 12 months
• Ability to tolerate target dose of enalapril (10 mg twice daily) and subsequently ARNI (valsartan/sacubitril 200 mg twice daily)

Post-Myocardial Infarction Considerations

For patients with AMI and left ventricular systolic dysfunction (LVSD), the ARNI valsartan/sacubitril is recognized as containing an ARB component and fulfills measure criteria if prescribed. 6

• An ACEI should not be added to AMI patients already treated with an ARNI given the increased risk of angioedema and other complications 6
• The efficacy of ARNI in patients with LV dysfunction and HF in the early post-MI period remains uncertain pending results of the PARADISE-MI trial 4

Critical Contraindications and Precautions

Absolute Contraindications 5, 1

• History of angioedema related to previous ACE inhibitor or ARB therapy
• Concomitant use with ACE inhibitors (requires 36-hour washout period when switching from ACEI to ARNI)
• Concomitant use with aliskiren in patients with diabetes
• Pregnancy (Boxed Warning: can cause injury and death to developing fetus)
• Hypersensitivity to any component

Dose Adjustments Required 5

• Severe renal impairment (eGFR <30 mL/min/1.73 m²): Reduce starting dose to 24/26 mg twice daily 5
• Moderate hepatic impairment (Child-Pugh B): Reduce starting dose to 24/26 mg twice daily 5
• Systolic blood pressure <100 mm Hg: Use with caution 5
• Elderly patients (age ≥75 years): Consider starting with 24/26 mg twice daily 5

Monitoring Requirements 5, 7

• Blood pressure (increased risk of symptomatic hypotension)
• Renal function (serum creatinine)
• Serum potassium levels (risk of hyperkalemia)
• Close follow-up and serial assessments recommended, especially with de novo initiation 5

Common Pitfalls to Avoid

Do not delay ARNI initiation waiting for aldosterone antagonist therapy - lack of treatment with an aldosterone antagonist should not delay initiating or switching a patient to an ARNI 5

Ensure adequate washout when switching from ACEI - a 36-hour washout period must be strictly observed when transitioning from an ACEI to an ARNI to avoid angioedema; this delay is not required when switching from an ARB 5

Avoid in volume-depleted patients - ensure patients are not volume-depleted before initiation, as up to 25% of patients in PIONEER-HF developed hypotension 5