What is the role of Entresto (sacubitril and valsartan) in treating chronic heart failure?

Role of Entresto (Sacubitril/Valsartan) in Treating Chronic Heart Failure

Entresto (sacubitril/valsartan) 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 cardiovascular death and heart failure hospitalization.

Indications and Patient Selection

Entresto is indicated for:

• Heart failure with reduced ejection fraction (HFrEF)
  • FDA-approved for patients with chronic heart failure and reduced ejection fraction 1
  • Recommended for patients with LVEF ≤40% 2
  • NYHA class II-IV symptoms 2, 3

Mechanism of Action

Entresto combines:

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

This dual mechanism enhances the natriuretic peptide system while simultaneously suppressing the renin-angiotensin-aldosterone system 3.

Clinical Evidence

The recommendation for Entresto is based primarily on the PARADIGM-HF trial, which demonstrated:

• 20% reduction in cardiovascular death compared to enalapril 3
• 21% reduction in heart failure hospitalizations 4
• 16% reduction in all-cause mortality 4
• Overall 20% risk reduction in the primary composite endpoint of cardiovascular death or heart failure hospitalization 2

Additionally, the PROVE-HF study showed significant cardiac remodeling benefits:

• Median LVEF increased from 28.2% to 37.8% after 12 months 2
• Significant reductions in left ventricular volumes 2

Treatment Algorithm for HFrEF

1. First-line therapy: ACE inhibitor/ARB + Beta-blocker + MRA
2. Optimization: Replace ACE inhibitor/ARB with Entresto if patient remains symptomatic despite optimal treatment with first-line therapy
3. Additional therapy: Consider adding SGLT2 inhibitor (dapagliflozin or empagliflozin)

Practical Implementation

Patient Selection Criteria:

• LVEF ≤40% 2
• NYHA class II-IV symptoms 2
• Currently on stable doses of ACE inhibitor/ARB
• Systolic blood pressure >100 mmHg

Contraindications:

• History of angioedema
• Severe renal impairment (eGFR <30 mL/min/1.73m²)
• Systolic blood pressure <100 mmHg
• Current decompensated heart failure
• Concomitant use of ACE inhibitors (requires 36-hour washout period)

Dosing Considerations:

• Start at lower doses in patients not previously on ACE inhibitor/ARB
• Target dose is 97/103 mg twice daily
• Monitor for hypotension, which is the most common side effect (14% vs. 9.2% with enalapril) 2

Important Caveats

1. Gap between trial and real-world populations: The PARADIGM-HF trial had strict inclusion criteria, but the FDA approval is broader. A study showed that many real-world patients eligible for Entresto per FDA criteria would not have qualified for the PARADIGM-HF trial 2.

2. Side effect management: Symptomatic hypotension is the most common side effect but typically doesn't lead to worsening renal function 2.

3. Transitioning from ACE inhibitors: A 36-hour washout period is required when switching from an ACE inhibitor to Entresto to minimize angioedema risk.

4. Real-world eligibility: Studies suggest that approximately 38% of patients with HFrEF on guideline-directed medical therapy may be eligible for sacubitril/valsartan 5.

Integration with Other Heart Failure Therapies

Entresto should be used as part of comprehensive heart failure management:

• Multidisciplinary heart failure management program is recommended 2
• Can be combined with beta-blockers, MRAs, and SGLT2 inhibitors 2
• For eligible patients, device therapy (ICD, CRT) should still be considered based on guideline criteria 2

Entresto represents a significant advancement in heart failure pharmacotherapy, offering improved outcomes compared to traditional ACE inhibitor therapy for patients with HFrEF.