What is the recommended dosing regimen for sacubitril valsartan in a patient with heart failure with reduced ejection fraction?

Sacubitril/Valsartan Dosing Regimen for Heart Failure with Reduced Ejection Fraction

Start sacubitril/valsartan at 49/51 mg twice daily for most patients, then double the dose every 2-4 weeks to reach the target maintenance dose of 97/103 mg twice daily. 1, 2

Initial Dosing Strategy

Standard Starting Dose:

• 49/51 mg twice daily for patients previously on high-dose ACE inhibitors or ARBs 1, 3, 2

Reduced Starting Dose (24/26 mg twice daily) for high-risk patients: 1, 3, 2

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Moderate hepatic impairment (Child-Pugh B)
• Age ≥75 years
• Patients on low/medium-dose ACE inhibitors or ARBs
• Treatment-naïve patients (no prior ACE inhibitor/ARB exposure)
• Systolic blood pressure ≤100 mmHg

Critical Transition Requirements

Mandatory 36-hour washout period when switching from an ACE inhibitor to sacubitril/valsartan to prevent angioedema. 1, 3, 2 This is an absolute requirement and cannot be shortened.

No washout period is required when switching from an ARB to sacubitril/valsartan. 1 You can initiate immediately after the last ARB dose.

Titration Schedule

Double the dose every 2-4 weeks as tolerated until reaching the target dose of 97/103 mg twice daily. 1, 3, 2 The target dose provides maximum mortality benefit based on the PARADIGM-HF trial, which demonstrated a 20% reduction in cardiovascular death or heart failure hospitalization compared to enalapril. 4, 1

Approximately 50% of patients achieve target dose within 10 weeks when initiated in-hospital or shortly after discharge. 1

Managing Common Barriers to Optimal Dosing

Hypotension Management

Asymptomatic hypotension (even with systolic BP <110 mmHg) is NOT a reason to reduce dose or avoid uptitration. 4, 1, 3 The drug maintains efficacy and safety regardless of baseline blood pressure. 4

For symptomatic hypotension: 1, 3

• First, ensure the patient is not volume-depleted
• Consider reducing loop diuretic doses in non-congested patients
• Only if necessary, temporarily reduce sacubitril/valsartan dose, then re-titrate upward
• Patient education about expected blood pressure changes is essential 3

Renal Function Considerations

Patients with renal dysfunction (eGFR ≥30 to <60 mL/min/1.73 m²) can safely initiate sacubitril/valsartan and often show improvements in eGFR (mean increase of 4.1 mL/min/1.73 m²). 5 Start at 24/26 mg twice daily in severe renal impairment. 1, 2

Laboratory Monitoring

Monitor blood pressure, renal function, and serum potassium at baseline and regularly during titration. 4 Exercise particular caution when potassium >5.0 mEq/L, especially when combined with mineralocorticoid receptor antagonists. 4

Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment. 4

Common Pitfalls to Avoid

Do not permanently reduce doses due to asymptomatic hypotension or mild laboratory changes. 1, 3 These do not predict adverse outcomes. Instead, use temporary dose reductions with subsequent re-titration. 4, 3

Do not fail to uptitrate to target doses. 4, 3 Medium-range doses do not provide the same mortality benefit as target doses. 4 The target dose of 97/103 mg twice daily is where maximum clinical benefit occurs. 1

Do not avoid initiation in NYHA class IV patients. 4, 1 While data are more limited in this population, sacubitril/valsartan remains indicated. 4

Special Populations

In-hospital initiation after hemodynamic stabilization is feasible and recommended. 4, 3 Resolution of acute pulmonary congestion should be achieved before initiating. 4

Elderly patients, those with recent heart failure hospitalization, and those with signs of congestion can safely receive sacubitril/valsartan, with benefits occurring within weeks of initiation. 1 Start at 24/26 mg twice daily in patients ≥75 years. 1, 2

Alternative Dosing for Very Low Tolerance

For patients considered by the treating physician likely to be intolerant of standard dosing, initiation at 25 mg twice daily (a very low dose not in the FDA label) has been used in real-world practice with similar decreases in NT-proBNP and increases in left ventricular ejection fraction. 6 However, the FDA-approved lowest dose remains 24/26 mg twice daily. 2