What is the role of Entresto (sacubitril/valsartan) in treating heart failure with reduced ejection fraction (HFrEF)?

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

Sacubitril/valsartan (Entresto) is strongly recommended as a replacement for ACE inhibitors or ARBs in patients with heart failure with reduced ejection fraction (HFrEF) to reduce the risk of heart failure hospitalization and death. 1, 2

Indications

• 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
• Indicated for patients with symptomatic HFrEF who remain symptomatic despite optimal medical therapy with an ACE inhibitor/ARB, beta-blocker, and mineralocorticoid receptor antagonist 1, 2
• Also approved for treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older 3

Mechanism of Action

• Combination of neprilysin inhibitor (sacubitril) and angiotensin receptor blocker (valsartan) 2, 4
• Provides simultaneous neprilysin inhibition and angiotensin II receptor blockade 4
• Enhances beneficial neurohormonal pathways while inhibiting harmful ones 2

Clinical Benefits in HFrEF

• Superior to ACE inhibitors in reducing:
  • Cardiovascular mortality 2, 4
  • Heart failure hospitalizations 1, 2
  • All-cause mortality 4, 5
  • Disease progression 4
• Provides consistent benefits regardless of heart failure duration, with improvements in:
  • Cardiac biomarkers (NT-proBNP, high-sensitivity troponin T, soluble ST2) 6
  • Health status measures 6
  • Cardiac remodeling with improved ejection fraction 6

Placement in Treatment Algorithm for HFrEF

1. First-line therapy: ACE inhibitor + beta-blocker 2
2. Second-line therapy: Add mineralocorticoid receptor antagonist (MRA) if patient remains symptomatic 2
3. Third-line therapy: Replace ACE inhibitor/ARB with sacubitril/valsartan if patient remains symptomatic despite optimal therapy with the above medications 1, 2
4. Consider additional therapies (SGLT2 inhibitors, ivabradine, device therapy) as appropriate 1

Dosing Considerations

• Adults: Start with 49/51 mg twice daily, titrate to target dose of 97/103 mg twice daily after 2-4 weeks as tolerated 3
• Pediatric patients: Dose based on weight (see specific dosing table in prescribing information) 3
• Allow 36-hour washout period when switching from ACE inhibitor to sacubitril/valsartan to reduce risk of angioedema 3

Safety Considerations

• Contraindications:

  • Concomitant use with ACE inhibitors (36-hour washout period required) 3
  • History of angioedema related to previous ACE inhibitor or ARB therapy 3
  • Pregnancy (discontinue when pregnancy detected due to fetal toxicity) 3

• Common adverse effects:

  • Symptomatic hypotension (more common than with ACE inhibitors) 4, 5
  • Hyperkalemia 7
  • Renal dysfunction 7
  • Cough 4

• Monitoring recommendations:

  • Blood pressure (watch for hypotension) 5
  • Renal function 7
  • Potassium levels 7

Expanding Role in Other Heart Failure Populations

• Emerging evidence supports potential benefits in:
  • Heart failure with mildly reduced ejection fraction (HFmrEF, LVEF 41-49%) 2, 7
  • Heart failure with preserved ejection fraction (HFpEF) 1, 7
  • Advanced heart failure (NYHA class IV) - limited data but being studied 8

Practical Considerations

• May need to adjust doses of concomitant medications:

  • Diuretics (may need dose reduction due to enhanced natriuresis) 1
  • Statins (may increase levels of certain statins; consider dose adjustments) 2

• Potential barriers to use:

  • Cost/insurance coverage
  • Hypotension (especially in elderly or volume-depleted patients) 5
  • Need for medication reconciliation and patient education when switching from ACE inhibitor/ARB

Summary

Sacubitril/valsartan represents a significant advancement in HFrEF treatment, offering mortality and morbidity benefits beyond traditional RAAS inhibition. It should be considered as replacement therapy for ACE inhibitors or ARBs in patients with HFrEF who remain symptomatic despite optimal medical therapy, with careful attention to proper dosing, monitoring, and management of potential side effects.