What is the role of Sacubitril (Angiotensin Receptor Neprilysin Inhibitor) Valsartan in treating heart failure with reduced ejection fraction?

Role of Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction

Sacubitril/valsartan is recommended as a replacement for ACE inhibitors to further reduce the risk of heart failure hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACE inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist. 1

Mechanism and Indications

• Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that combines the neprilysin inhibitor sacubitril with the angiotensin receptor blocker valsartan 2
• FDA-approved to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure and reduced ejection fraction 3
• The drug is specifically indicated for patients with symptomatic HFrEF despite optimal medical therapy 1

Clinical Benefits in HFrEF

• Reduces risk of heart failure hospitalization and death compared to ACE inhibitors 1
• Improves left ventricular ejection fraction (from 27% to approximately 30%) 4
• Decreases NT-proBNP levels, indicating reduced cardiac wall stress 4
• Improves NYHA functional class, allowing reduction in diuretic doses 4
• Enhances exercise tolerance with improved peak oxygen consumption (VO₂) and ventilatory efficiency 5
• Reduces moderate to severe mitral regurgitation (from 30.1% to 17.4%) 4

Placement in Treatment Algorithm for HFrEF

1. First-line therapy: ACE inhibitor + beta-blocker 1
2. Second-line: Add mineralocorticoid receptor antagonist (MRA) if patient remains symptomatic 1
3. Third-line: Replace ACE inhibitor with sacubitril/valsartan if patient remains symptomatic despite optimal therapy with the above medications 1

Important Prescribing Considerations

• Washout period: Allow 36 hours between last dose of ACE inhibitor and first dose of sacubitril/valsartan to minimize risk of angioedema 3
• Starting dose: 49/51 mg orally twice daily for most adult patients 3
• Target dose: Titrate to 97/103 mg twice daily after 2-4 weeks as tolerated 3
• Monitoring: Blood pressure, renal function, potassium levels, and signs of hypotension 3

Potential Drug Interactions

• May increase levels of statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters 1
• Lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin may be considered when used in combination with sacubitril/valsartan 1

Emerging Evidence in Other HF Populations

• May provide benefits in heart failure with mildly reduced ejection fraction (HFmrEF, LVEF 41-49%) 1, 6
• In HFpEF (LVEF ≥50%), sacubitril/valsartan has shown:
  • Reduction in heart failure hospitalizations 7
  • Improvement in NYHA classification 6, 7
  • Reduction in NT-proBNP levels 7
  • No significant impact on cardiovascular or all-cause mortality 6, 7

Contraindications and Precautions

• Contraindicated with concomitant use of ACE inhibitors due to increased risk of angioedema 3
• Contraindicated in pregnancy due to fetal toxicity 3
• Use caution in patients with:
  • Severe renal impairment (eGFR <30 mL/min/1.73m²) 3
  • History of angioedema 3
  • Hypotension (more common with sacubitril/valsartan than with ACE inhibitors or ARBs alone) 6

Implementation Challenges

• Despite guideline recommendations, sacubitril/valsartan remains underutilized in eligible patients 2
• Barriers include practitioner unfamiliarity, safety concerns, and reimbursement issues 2
• Gradual introduction using a treatment sequence scheme may improve implementation 2