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 and reduced ejection fraction (HFrEF), and for treating symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. 1

Primary FDA-Approved Indications

Heart Failure with Reduced Ejection Fraction (HFrEF) in Adults

• Entresto is indicated for adult patients with chronic heart failure and reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization 1
• The drug is specifically recommended for patients with NYHA class II-IV symptoms and LVEF ≤40% 2, 3
• Entresto can be initiated in patients who remain symptomatic despite optimal medical therapy with ACE inhibitors, beta-blockers, and mineralocorticoid receptor antagonists 2

Pediatric Heart Failure

• Entresto is approved for treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older 1
• The medication reduces NT-proBNP and is expected to improve cardiovascular outcomes in this population 1

Clinical Positioning in Treatment Algorithm

Replacement for ACE Inhibitors/ARBs

• Entresto should replace ACE inhibitors or ARBs in patients with HFrEF who remain symptomatic on guideline-directed medical therapy, rather than waiting for patients to "fail" optimal therapy first 2, 3
• The 2022 ACC/AHA/HFSA guidelines give Entresto a Class I recommendation for patients with symptomatic HFrEF who are tolerating adequate doses of ACE inhibitors or ARBs 2
• Entresto demonstrated a 20% relative reduction in the composite endpoint of cardiovascular death or heart failure hospitalization compared to enalapril 2

De Novo Initiation

• Entresto may be initiated directly without prior ACE inhibitor or ARB therapy in patients with chronic symptomatic HFrEF 2
• The PIONEER-HF trial demonstrated that Entresto can be safely initiated in hospitalized patients with acute decompensated HFrEF before discharge 2
• De novo initiation simplifies management and has shown similar efficacy and safety compared to patients previously on ACE inhibitors or ARBs 2, 3

Expanded Indications Under Investigation

Heart Failure with Preserved Ejection Fraction (HFpEF)

• The FDA approved sacubitril/valsartan for selected patients with HFpEF based on the PARAGON-HF trial 4
• The 2022 ACC/AHA/HFSA guidelines give Entresto a Class 2b recommendation for HFpEF, particularly for patients with LVEF 45-57% and women 4
• In the PARAGON-HF trial, patients with LVEF below the median (45-57%) showed significant benefit with a rate ratio of 0.78 (95% CI 0.64-0.95) 4
• Women with HFpEF experienced significant benefit with a rate ratio of 0.73 (95% CI 0.59-0.90), primarily driven by reduction in heart failure hospitalizations 4

Post-Myocardial Infarction

• The ongoing PARADISE-MI trial is evaluating whether sacubitril/valsartan reduces cardiovascular death and heart failure hospitalization in patients after acute MI with LVEF ≤40% and/or pulmonary congestion 2
• At present, the efficacy of Entresto in patients with LV dysfunction and heart failure in the early post-MI period remains uncertain 2

Key Contraindications and Precautions

Absolute Contraindications

• History of angioedema related to previous ACE inhibitor or ARB therapy 1
• Concomitant use with ACE inhibitors (requires 36-hour washout period) 1, 3
• Concomitant use with aliskiren in patients with diabetes 1
• Hypersensitivity to any component 1
• Pregnancy (causes fetal toxicity) 1

Relative Contraindications and Cautions

• Severe hepatic impairment (use not recommended) 1
• Systolic blood pressure <100 mm Hg requires careful monitoring, though lower BP is not an absolute contraindication 3
• Severe renal impairment (eGFR <30 mL/min/1.73 m²) requires dose reduction to 24/26 mg twice daily 3, 1
• Moderate hepatic impairment (Child-Pugh B) requires starting dose of 24/26 mg twice daily 3, 1

Clinical Benefits Across Disease Duration

• Entresto provides benefits regardless of heart failure duration, with significant improvements in biomarkers, health status, and cardiac remodeling occurring in patients with HF duration <12 months, 12-24 months, 24-60 months, and >60 months 5
• Patients with newer onset HFrEF (<12 months) showed absolute LVEF improvement of 12.2% by 12 months, while those with longer disease duration (>60 months) still achieved 8.6% improvement 5