What is the role of Entresto (sacubitril/valsartan) in heart failure management?

Role of Entresto (Sacubitril/Valsartan) in Heart Failure Management

Entresto (sacubitril/valsartan) is recommended as a first-line therapy to replace ACE inhibitors or ARBs in patients with heart failure with reduced ejection fraction (HFrEF) to significantly reduce morbidity and mortality. 1

Mechanism and Indications

Entresto is a first-in-class medication that combines:

• Sacubitril: A neprilysin inhibitor that prevents breakdown of natriuretic peptides
• Valsartan: An angiotensin receptor blocker (ARB)

This dual mechanism enhances beneficial vasodilatory peptides while blocking the harmful effects of angiotensin II, providing superior neurohormonal modulation compared to ACE inhibitors or ARBs alone 2.

FDA-approved indications 3:

• To reduce the risk of cardiovascular death and hospitalization for heart failure in adults with chronic heart failure
• Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal
• For treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older

Clinical Evidence and Recommendations

The 2022 AHA/ACC/HFSA guidelines provide a Class I recommendation (Level of Evidence B-R) for Entresto based on strong evidence of clinical benefit 1:

• In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by Entresto is recommended to further reduce morbidity and mortality
• Entresto is recommended as de novo treatment in hospitalized patients with acute heart failure before discharge
• Entresto may be initiated de novo in patients with symptomatic chronic HFrEF to simplify management

The PARADIGM-HF trial demonstrated that Entresto significantly reduced:

• Composite endpoint of cardiovascular death or heart failure hospitalization by 20%
• Cardiovascular mortality by 20%
• Heart failure hospitalizations by 21%
• All-cause mortality by 16% 1, 4

Practical Implementation

Dosing:

• Starting dose: 24/26 mg twice daily
• Target dose: 97/103 mg twice daily 5, 3
• Dose adjustment may be needed for patients with:
  • Renal impairment
  • Systolic blood pressure ≤100 mmHg
  • Not previously taking ACE inhibitors or ARBs

Important Precautions:

1. Do not administer with ACE inhibitors - Allow a 36-hour washout period between ACE inhibitor discontinuation and Entresto initiation 1, 3
2. Contraindicated in patients with history of angioedema 1, 3
3. Monitor for hypotension - More common with Entresto than with ACE inhibitors 1
4. Pregnancy risk - Can cause fetal harm; contraindicated in pregnancy 3

Integration into Heart Failure Treatment Algorithm

For New HFrEF Diagnosis:

1. Consider initiating Entresto as first-line therapy (de novo approach) rather than starting with ACE inhibitor/ARB 1
2. Combine with other core medications for HFrEF:
   • Beta-blocker (carvedilol, metoprolol succinate, or bisoprolol)
   • Mineralocorticoid receptor antagonist (spironolactone or eplerenone)
   • SGLT2 inhibitor (dapagliflozin or empagliflozin) 5

For Patients Already on ACE inhibitor/ARB:

1. Switch to Entresto if patient:

   • Has NYHA class II-III symptoms
   • Has LVEF ≤40%
   • Tolerates current ACE inhibitor/ARB therapy
   • Has systolic BP >100 mmHg 1

2. Do not switch if patient:

   • Has history of angioedema
   • Has severe renal impairment
   • Is pregnant or planning pregnancy
   • Has persistently low blood pressure 3

Common Pitfalls and Solutions

1. Hypotension management:

   • Consider reducing diuretic dose in non-congested patients
   • Monitor blood pressure closely after initiation
   • Start at lower dose (24/26 mg BID) in patients with borderline blood pressure 1

2. Medication sequencing errors:

   • Ensure 36-hour washout between ACE inhibitor and Entresto
   • Never administer ACE inhibitor and Entresto simultaneously 1, 3

3. Underutilization:

   • Despite guideline recommendations, real-world studies show only about 38% of eligible HFrEF patients receive Entresto 6
   • Consider Entresto in all appropriate patients to improve outcomes

4. Monitoring requirements:

   • Check renal function and electrolytes before initiation and 1-2 weeks after starting or titrating
   • Monitor blood pressure regularly, especially during dose titration 5

Entresto represents a significant advancement in heart failure therapy, with clear evidence of superiority over ACE inhibitors in reducing mortality and hospitalizations in HFrEF patients. Its integration into guideline-directed medical therapy has established it as a cornerstone treatment for heart failure management.