What is the recommended treatment and dosage for patients with heart failure with reduced ejection fraction using Entresto (sacubitril/valsartan)?

Entresto (Sacubitril/Valsartan) for Heart Failure with Reduced Ejection Fraction

Indications

Entresto is indicated for patients with HFrEF (EF ≤40%) with NYHA class II-IV symptoms and should replace ACE inhibitors or ARBs in symptomatic patients already on optimal medical therapy (beta-blocker and mineralocorticoid receptor antagonist). 1, 2

• Entresto reduces the risk of heart failure hospitalization and death compared to ACE inhibitors in patients with symptomatic HFrEF despite optimal medical therapy 1
• The European Society of Cardiology recommends sacubitril/valsartan as third-line therapy after ACE inhibitor/ARB + beta-blocker (first-line) and mineralocorticoid receptor antagonist (second-line) 1
• Recent evidence supports direct initiation of sacubitril/valsartan without pretreatment with ACE inhibitors or ARBs as a safe and effective strategy 1

Dosing Algorithm

Standard Dosing (Patients on High-Dose ACE Inhibitors)

• Start at 49/51 mg twice daily 3
• Double the dose every 2-4 weeks to target maintenance dose of 97/103 mg twice daily 1, 3

Low Starting Dose (Multiple Scenarios)

Start at 24/26 mg twice daily if the patient has ANY of the following: 1, 3

• Not currently taking an ACE inhibitor or ARB (de novo)
• Previously on low/medium-dose ACE inhibitors or ARBs
• Severe renal impairment (eGFR <30 mL/min/1.73m²)
• Moderate hepatic impairment (Child-Pugh B)
• Age ≥75 years
• Systolic blood pressure ≤100 mm Hg

Then titrate upward every 2-4 weeks as tolerated to reach 97/103 mg twice daily 1, 3

Critical Safety Requirements

Mandatory 36-Hour Washout from ACE Inhibitors

You must discontinue ACE inhibitors and wait 36 hours before initiating Entresto to avoid angioedema. 1, 2, 3

• No washout period is required when switching from an ARB 1
• Concomitant use with ACE inhibitors is absolutely contraindicated 3

Contraindications

• History of angioedema with ACE inhibitor or ARB therapy (relative contraindication requiring caution) 1
• Concomitant ACE inhibitor use 3

Medication Management During Initiation

Continue These Medications

• Beta-blockers (e.g., metoprolol succinate) must be continued as cornerstone therapy 2
• Mineralocorticoid receptor antagonists (spironolactone or eplerenone) should be continued 1

Consider Adjusting These Medications

• Reduce diuretic doses in non-congested patients due to enhanced natriuresis with Entresto 1, 2
• Consider lower doses of statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) as sacubitril/valsartan increases levels of statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters 1

Monitoring Protocol

Initial Monitoring (Within 1-2 Weeks After Initiation and Each Dose Increase)

• Check renal function and electrolytes 2
• Monitor blood pressure closely, especially during initiation and dose titration 2

Managing Common Side Effects

Hypotension Management:

• If symptomatic hypotension occurs, consider temporary dose reduction rather than discontinuation 1, 2
• 40% of patients who required temporary dose reduction were subsequently restored to target doses 1
• Symptomatic hypotension can usually be managed through patient education and counseling without reducing therapy 1
• In non-congested patients, reduce diuretic doses to mitigate hypotensive effects 1

Renal Function:

• Severe renal impairment requires dose adjustment (start at 24/26 mg twice daily), not avoidance 1, 2
• Entresto improves left ventricular systolic and diastolic function even in patients with end-stage kidney disease 4

Critical Pitfalls to Avoid

• Do not underdose due to asymptomatic hypotension or mild laboratory changes - benefits are dose-dependent and maximum mortality benefit occurs at target dose of 97/103 mg twice daily 1, 2
• Do not make permanent dose reductions when temporary reductions with subsequent re-titration would be more appropriate 1
• Do not fail to titrate to target doses - medium-range doses do not provide most of the benefits of target doses 1
• Do not discontinue therapy prematurely due to mild laboratory changes or asymptomatic hypotension 2
• Do not neglect the 36-hour washout period when switching from ACE inhibitors 2, 3

Special Populations

• Entresto remains indicated in patients with NYHA class IV symptoms, though data in this population are limited 1
• Benefits occur regardless of heart failure duration, with improvements in biomarkers, health status, and cardiac remodeling even in patients with HF duration >60 months 5