Where does Entresto (sacubitril/valsartan) fit in the treatment of heart failure with reduced ejection fraction (HFrEF)?

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

Entresto (sacubitril/valsartan) should replace ACE inhibitors or ARBs in patients with HFrEF who remain symptomatic at NYHA class II-III despite optimal medical therapy for at least 3 months. 1

Position in Treatment Algorithm

Entresto represents a significant advancement in heart failure management, specifically designed for patients with heart failure with reduced ejection fraction (HFrEF). The medication works through a dual mechanism:

1. Sacubitril: Neprilysin inhibitor
2. Valsartan: Angiotensin II receptor blocker

Indications for Entresto

• Adult patients with chronic HFrEF (LVEF ≤40%)
• Patients who remain symptomatic (NYHA class II-III) despite at least 3 months of optimal therapy with ACE inhibitor or ARB 1
• Target population: Those at risk for cardiovascular death and hospitalization for heart failure

Dosing Recommendations

• Starting dose: 49/51 mg orally twice daily
• Target maintenance dose: 97/103 mg orally twice daily 2
• Dose adjustment every 2-4 weeks to target maintenance dose as tolerated
• Reduced starting dose (24/26 mg twice daily) for:
  • Patients with severe renal impairment
  • Patients with moderate hepatic impairment 2

Evidence Supporting Use

The 2020 ACC/AHA guidelines strongly recommend Entresto based on evidence showing:

• 20% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization compared to enalapril 1
• Benefits seen consistently across subgroups
• Similar extent of benefit for both death and heart failure hospitalization 1

Multiple studies support the use of Entresto, including:

• Clinical trials
• Meta-analyses
• Observational clinical effectiveness studies 1

Placement in Treatment Sequence

The current treatment algorithm for HFrEF places Entresto as a replacement for ACE inhibitors or ARBs:

1. Initial therapy: Beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors
2. Replacement therapy: Entresto to replace ACE inhibitors or ARBs in eligible patients 1
3. Additional therapies: Consider ivabradine for patients with heart rate ≥70 bpm despite optimal therapy

Contraindications and Precautions

Entresto is contraindicated in:

• Patients with hypersensitivity to any component
• History of angioedema related to previous ACE inhibitor or ARB therapy
• Concomitant use with ACE inhibitors (36-hour washout period required)
• Concomitant use with aliskiren in patients with diabetes 2

Monitor for:

• Signs and symptoms of angioedema
• Hypotension
• Renal function and potassium levels in susceptible patients 2

Common Adverse Effects

The most common adverse reactions (≥5%) include:

• Hypotension
• Hyperkalemia
• Cough
• Dizziness
• Renal failure 2

Special Considerations

• Pregnancy: Contraindicated due to fetal toxicity risk (boxed warning)
• Breastfeeding: Not recommended
• Severe hepatic impairment: Not recommended 2
• Drug interactions: Avoid concomitant use with potassium-sparing diuretics, NSAIDs, and lithium

Clinical Implementation

For optimal implementation:

1. Identify eligible patients with HFrEF (LVEF ≤40%) who remain symptomatic despite ACE inhibitor/ARB therapy
2. Discontinue ACE inhibitor at least 36 hours before initiating Entresto
3. Start with appropriate dose based on renal/hepatic function
4. Titrate dose every 2-4 weeks as tolerated
5. Monitor blood pressure, renal function, and potassium levels
6. Continue other guideline-directed medical therapies (beta-blockers, MRAs, SGLT2 inhibitors)

Common Pitfalls to Avoid

• Failure to discontinue ACE inhibitors: Must wait 36 hours after last ACE inhibitor dose before starting Entresto to reduce angioedema risk
• Inadequate dose titration: Many patients remain on suboptimal doses; aim for target dose of 97/103 mg twice daily when tolerated
• Overlooking eligible patients: Consider Entresto for all symptomatic HFrEF patients despite optimal ACE inhibitor/ARB therapy
• Inappropriate discontinuation: Benefits of Entresto are sustained long-term; continue therapy even if symptoms improve 3

By following these guidelines, Entresto can be appropriately integrated into the treatment regimen for patients with HFrEF to reduce mortality and hospitalization risk.