Entresto (Sacubitril/Valsartan) in Cardiomyopathy
Yes, Entresto is strongly recommended for patients with cardiomyopathy causing heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%), where it reduces cardiovascular death and heart failure hospitalization more effectively than ACE inhibitors. 1, 2, 3
Primary Indication: HFrEF
Entresto is FDA-approved and guideline-recommended specifically for chronic heart failure with reduced ejection fraction (LVEF below normal, typically ≤40%). 2, 1 The drug is indicated for patients with NYHA class II-IV symptoms who remain symptomatic despite optimal medical therapy with ACE inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. 1, 3
Treatment Algorithm for HFrEF
The European Society of Cardiology recommends a stepwise approach: 1
- First-line: ACE inhibitor + beta-blocker 1
- Second-line: Add mineralocorticoid receptor antagonist (MRA) if symptomatic 1
- Third-line: Replace ACE inhibitor with sacubitril/valsartan if still symptomatic 1
- Additional therapy: SGLT2 inhibitor (dapagliflozin or empagliflozin) to reduce hospitalization and death 1
Clinical Benefits in HFrEF
Sacubitril/valsartan provides superior outcomes compared to ACE inhibitors in HFrEF patients: 3
- 20% reduction in cardiovascular death or heart failure hospitalization compared to enalapril 1, 3
- Reduces all-cause mortality 3
- Improves cardiac remodeling with increased left ventricular ejection fraction and decreased left ventricular volumes 1
- Benefits occur regardless of heart failure duration, even in patients with disease lasting more than 60 months 4
Dosing Strategy
Initial Dosing
Start dose depends on prior therapy: 1
- 49/51 mg twice daily: Patients previously on high-dose ACE inhibitors 1
- 24/26 mg twice daily: Patients on low/medium-dose ACE inhibitors or ARBs, treatment-naïve patients, severe renal impairment (eGFR <30 mL/min/1.73 m²), moderate hepatic impairment, or age ≥75 years 1, 2
Titration Schedule
Double the dose every 2-4 weeks as tolerated to reach target dose of 97/103 mg twice daily, which provides maximum mortality benefit. 1
Critical Safety Requirement
A mandatory 36-hour washout period is required when switching from an ACE inhibitor to avoid angioedema. 1, 2 No washout is needed when switching from an ARB. 1
Managing Common Barriers
Hypotension
- Asymptomatic hypotension is not a reason to avoid initiation or uptitration 1
- Sacubitril/valsartan maintains efficacy even with systolic BP <110 mmHg 1
- If symptomatic hypotension occurs, reduce diuretic dose first before reducing sacubitril/valsartan 1
- Consider temporary dose reduction rather than permanent discontinuation; 40% of patients requiring temporary reduction can be restored to target doses 1
Renal Function
- Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment 1
- Monitor renal function and electrolytes, particularly when used with aldosterone antagonists 1
Use in Other Cardiomyopathy Populations
Heart Failure with Mildly Reduced EF (HFmrEF, LVEF 41-49%)
The American College of Cardiology suggests sacubitril/valsartan may provide benefits in HFmrEF (Class 2b recommendation). 1 Recent evidence shows improvements in KCCQ scores, NYHA class, and composite outcomes of HF hospitalization and cardiovascular death. 5
Heart Failure with Preserved EF (HFpEF, LVEF ≥45%)
Sacubitril/valsartan has limited evidence in HFpEF and should not be first-line therapy. 6 The PARAGON-HF trial did not meet its primary endpoint (rate ratio 0.87,95% CI 0.75-1.01, p=0.06). 6 However, subgroup analyses showed potential benefit in:
- Women with HFpEF (rate ratio 0.73,95% CI 0.59-0.90) 6
- Patients with LVEF 45-57% (rate ratio 0.78,95% CI 0.64-0.95) 6
SGLT2 inhibitors should be prioritized over sacubitril/valsartan in most HFpEF patients (Class 2a vs. Class 2b recommendation). 6
Contraindications
Absolute contraindications per FDA labeling: 2
- History of angioedema related to previous ACE inhibitor or ARB therapy
- Concomitant use with ACE inhibitors
- Concomitant use with aliskiren in patients with diabetes
- Hypersensitivity to any component
Special Populations
Diabetes
The European Society of Cardiology recommends sacubitril/valsartan instead of ACE inhibitors in HFrEF patients with diabetes who remain symptomatic despite treatment with ACE inhibitors, beta-blockers, and MRAs. 7
Acute Heart Failure
The PIONEER trial demonstrated that initiation during acute HF hospitalization in stable HFrEF patients resulted in greater NT-proBNP reduction than enalapril without worse side effects. 7 Initiate after resolution of acute pulmonary congestion and hemodynamic stabilization. 1