What is the recommended dosage of valsartan (Angiotensin II Receptor Blocker) and sacubitril (Neprilysin inhibitor) for heart failure with reduced ejection fraction?

Sacubitril/Valsartan Dosing for Heart Failure with Reduced Ejection Fraction

Start sacubitril/valsartan at 49/51 mg twice daily for most patients, or 24/26 mg twice daily for those at higher risk (severe renal impairment, moderate hepatic impairment, age ≥75 years, or low/medium-dose prior ACE inhibitor/ARB exposure), then double the dose every 2-4 weeks to reach the target of 97/103 mg twice daily. 1, 2, 3

Initial Dosing Strategy

The starting dose depends on your patient's clinical profile:

Standard-risk patients (49/51 mg twice daily): 1, 2

• Previously on high-dose ACE inhibitor or ARB
• Systolic blood pressure ≥100 mmHg
• Normal renal function (eGFR ≥30 mL/min/1.73 m²)
• No hepatic impairment

High-risk patients (24/26 mg twice daily): 1, 2, 3

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Moderate hepatic impairment (Child-Pugh B)
• Age ≥75 years
• Previously on low or medium-dose ACE inhibitor/ARB
• De novo initiation (no prior ACE inhibitor/ARB exposure)
• Borderline blood pressure (systolic BP ≤100 mmHg)

Critical Transition Requirements

When switching from an ACE inhibitor, you must observe a mandatory 36-hour washout period to avoid angioedema. 1, 2, 3 This is an absolute requirement—no exceptions. When switching from an ARB, no washout period is needed and you can initiate sacubitril/valsartan immediately. 1, 4

Titration Schedule

Double the dose every 2-4 weeks as tolerated until reaching the target dose of 97/103 mg twice daily. 1, 2, 3 The target dose provides maximum mortality benefit based on the PARADIGM-HF trial, where the mean achieved dose was 182 mg sacubitril and 193 mg valsartan total daily (equivalent to approximately 91/96.5 mg twice daily). 1

The titration pathway is straightforward:

• 24/26 mg twice daily → 49/51 mg twice daily → 97/103 mg twice daily 2, 3

Approximately 50% of patients achieve target dose within 10 weeks when initiated in-hospital or shortly after discharge. 1, 2

Managing Common Barriers to Optimal Dosing

Hypotension Management

Asymptomatic hypotension is not a reason to reduce or avoid uptitration—the drug maintains efficacy and safety even with systolic BP <110 mmHg. 2, 4 This is a critical point where many clinicians unnecessarily stop titration.

For patients with symptomatic hypotension: 1, 2

• First, ensure the patient is not volume-depleted
• Consider empirically reducing loop diuretic doses in non-congested patients
• If needed, temporarily reduce sacubitril/valsartan dose, then re-titrate upward
• Avoid permanent dose reductions when temporary reductions would suffice

Up to 25% of patients may develop hypotension during initiation, but this can usually be managed without discontinuation. 1

Renal Function Changes

Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment. 4 In fact, sacubitril/valsartan improved eGFR by a mean of 4.1 mL/min/1.73 m² in patients with baseline renal dysfunction (eGFR 30-60 mL/min/1.73 m²) in the TRANSITION study. 5

For severe renal impairment (eGFR <30 mL/min/1.73 m²), start at half the usual dose (24/26 mg twice daily), then follow standard dose escalation. 1, 3

Hospital Initiation

In-hospital initiation after hemodynamic stabilization is feasible and should be pursued. 1, 2 The PIONEER-HF trial demonstrated safety and efficacy of in-hospital initiation in patients stabilized from acute decompensated heart failure. 6

Criteria for hemodynamic stabilization include: 4

• Resolution of acute pulmonary congestion
• Stable vital signs
• No requirement for intravenous vasodilators or inotropes

Common Pitfalls to Avoid

Do not fail to uptitrate due to asymptomatic hypotension or mild laboratory changes—these do not predict adverse outcomes. 2, 4 The most common error is accepting suboptimal doses when target doses could be achieved with appropriate management.

Do not make permanent dose reductions when temporary reductions with subsequent re-titration would be appropriate. 2, 4 In clinical trials, 40% of patients who required temporary dose reduction were successfully restored to target doses. 4

Do not delay initiation waiting for patients to "fail" optimal medical therapy first—all symptomatic HFrEF patients (NYHA class II-IV) are candidates for sacubitril/valsartan. 4 Recent evidence supports direct-to-ARNI initiation without prior ACE inhibitor/ARB exposure. 1, 4

Special Populations

Sacubitril/valsartan remains indicated in NYHA class IV patients, though data in this population are more limited. 1, 7 The drug maintains effectiveness in vulnerable populations including elderly patients, those with recent heart failure hospitalization, and those with signs of congestion, with benefits occurring within weeks of initiation. 4