What is the recommended use and dosage of sacubitril (Angiotensin Receptor Neprilysin Inhibitor) valsartan for patients with heart failure with reduced ejection fraction?

Sacubitril/Valsartan for Heart Failure with Reduced Ejection Fraction

Indications and Patient Population

Sacubitril/valsartan is indicated to reduce cardiovascular death and hospitalization in adult patients with chronic heart failure and reduced ejection fraction (HFrEF), typically defined as LVEF ≤40%. 1 The drug is FDA-approved for NYHA functional class II-IV patients with HFrEF, representing a broader population than was studied in the pivotal PARADIGM-HF trial. 2

The European Society of Cardiology recommends sacubitril/valsartan as a replacement for ACE inhibitors or ARBs in patients who remain symptomatic despite optimal medical therapy with an ACE inhibitor, beta-blocker, and mineralocorticoid receptor antagonist. 3 This represents a Class I recommendation with high-quality evidence supporting a 20% reduction in cardiovascular mortality compared to enalapril. 2

Treatment Algorithm and Positioning

Sacubitril/valsartan should be considered as third-line therapy after optimizing first-line (ACE inhibitor + beta-blocker) and second-line (adding mineralocorticoid receptor antagonist) treatments in symptomatic patients. 3, 4 However, recent evidence supports direct initiation without prior ACE inhibitor or ARB exposure as a safe and effective strategy. 2, 4

The treatment sequence recommended by the European Society of Cardiology is: 3

• First-line: ACE inhibitor + beta-blocker
• Second-line: Add mineralocorticoid receptor antagonist if symptomatic
• Third-line: Replace ACE inhibitor/ARB with sacubitril/valsartan if still symptomatic
• Additional therapy: SGLT2 inhibitor (dapagliflozin or empagliflozin) to further reduce hospitalization and death risk

Dosing and Titration

Starting Dose

The recommended starting dose is 49/51 mg twice daily for most adult patients. 1 However, specific populations require dose adjustment:

• Patients on high-dose ACE inhibitors: Start at 49/51 mg twice daily 3
• Patients on low/medium-dose ACE inhibitors or ARBs: Start at 24/26 mg twice daily 3
• De novo patients (no prior ACE inhibitor/ARB): Start at 24/26 mg twice daily 3
• Severe renal impairment (eGFR <30 mL/min/1.73 m²): Start at half the usual starting dose 1
• Moderate hepatic impairment (Child-Pugh B): Start at 24/26 mg twice daily 3
• Elderly patients (≥75 years): Start at 24/26 mg twice daily 3
• Borderline blood pressure (SBP ≤100 mmHg): Start at 24/26 mg twice daily 3

Titration Schedule

Double the dose every 2-4 weeks as tolerated to reach the target maintenance dose of 97/103 mg twice daily. 3, 1 This target dose provides maximum mortality benefit demonstrated in clinical trials. 3 Real-world data shows that only 17% of patients achieve target dose after 4 months, with half remaining on the starting dose. 5 This represents a critical gap in care, as medium-range doses do not provide most of the benefits of target doses. 3

Critical Washout Period

When switching from an ACE inhibitor to sacubitril/valsartan, a mandatory 36-hour washout period must be observed to avoid angioedema. 1, 3 This is a contraindication, not merely a precaution. 3 No washout period is required when switching from an ARB. 3

Managing Hypotension

Hypotension is the most common side effect, occurring in 16% of patients asymptomatically and 11% symptomatically. 4 However, the efficacy and safety of sacubitril/valsartan are maintained despite hypotension, with benefits consistent across all baseline systolic blood pressure categories, including <110 mmHg. 4

Key strategies to mitigate hypotension: 2, 4

• Ensure patients are not volume-depleted at initiation
• In non-congested patients with borderline blood pressure, empirically reduce loop diuretic doses
• For patients experiencing hypotension, temporarily reduce the dose rather than discontinuing completely—40% of patients requiring temporary dose reduction can subsequently be restored to target doses 3

Common pitfall to avoid: Do not permanently reduce doses due to asymptomatic hypotension or mild laboratory changes when temporary reductions with subsequent re-titration would be more appropriate. 3

Initiation During Hospitalization

Sacubitril/valsartan can be safely initiated during hospitalization for acute decompensated heart failure after hemodynamic stabilization, defined as resolution of acute pulmonary congestion. 2, 3 The PIONEER-HF trial demonstrated feasibility of in-hospital initiation, though up to 25% of patients developed hypotension. 2 Ensuring adequate volume status before initiation helps avoid this complication. 2

The TRANSITION study showed that approximately half of patients could achieve target dose within 10 weeks after in-hospital initiation or soon after discharge. 2

Special Populations and Considerations

Renal function: Sacubitril/valsartan increases eGFR compared to RAS inhibitors in patients with heart failure and chronic kidney disease. 6 Severe renal impairment requires dose adjustment, not avoidance. 3

NYHA Class IV patients: Although data are limited in this population, sacubitril/valsartan remains indicated for these higher-risk patients. 2

Heart failure duration: The drug decreases prognostic biomarkers, improves health status, and reverses cardiac remodeling regardless of heart failure duration, with benefits seen even in patients with HF duration >60 months. 7

Monitoring Requirements

Close follow-up with serial assessments is required after initiation, including: 4

• Blood pressure monitoring, especially in patients with borderline BP
• Electrolytes (particularly potassium when used with aldosterone antagonists)
• Renal function

Drug Interactions

Sacubitril/valsartan may increase levels of statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters. 3 Consider lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin when used in combination. 3

Clinical Outcomes

Real-world data demonstrates that sacubitril/valsartan is associated with significant improvements within 4 months of treatment: 5

• Reduction in all-cause inpatient stays from 27.5% to 17.0% (p=0.009)
• Decrease in fatigue from 51.8% to 39.5% (p=0.027)
• Reduction in shortness of breath from 66.7% to 51.8% (p=0.008)