How should sacubitril/valsartan be initiated, dosed, titrated, monitored, and what are its contraindications for an adult with chronic heart failure with reduced ejection fraction (≤40%) and NYHA class II‑IV symptoms who can tolerate an ACE inhibitor or ARB?

Sacubitril/Valsartan for Heart Failure with Reduced Ejection Fraction

Replace ACE inhibitors or ARBs with sacubitril/valsartan in all adults with chronic HFrEF (EF ≤40%) and NYHA class II-IV symptoms who can tolerate an ACE inhibitor or ARB, as this provides a 20% reduction in cardiovascular death and heart failure hospitalization compared to enalapril. 1

Patient Selection Criteria

Before initiating sacubitril/valsartan, confirm the patient meets these requirements:

• Left ventricular ejection fraction ≤40% 1
• NYHA functional class II-IV symptoms (predominantly class II-III; class IV patients have limited data) 1
• Currently tolerating an ACE inhibitor or ARB (or ACE/ARB-naïve patients can start directly) 1
• Systolic blood pressure ≥100 mm Hg at baseline 1
• eGFR ≥30 mL/min/1.73 m² 1
• Serum potassium ≤5.2 mmol/L 1
• No history of angioedema with prior ACE inhibitor or ARB therapy 1, 2

Initiation Protocol

Switching from ACE Inhibitor

Mandatory 36-hour washout period between the last ACE inhibitor dose and first sacubitril/valsartan dose to prevent angioedema. 1, 2 This is a Class I recommendation with strong evidence and represents an absolute contraindication to concurrent use. 1

Switching from ARB

No washout period required—switch directly from ARB to sacubitril/valsartan. 1

De Novo Initiation (ACE/ARB-Naïve)

Direct initiation is safe and effective without prior ACE inhibitor or ARB exposure, particularly in hospitalized patients with acute decompensated HF after hemodynamic stabilization. 1, 3

Dosing Algorithm

Standard Starting Dose

49/51 mg orally twice daily for most patients 1, 2

Reduced Starting Dose (24/26 mg twice daily)

Use the lower starting dose for patients with: 1, 2

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Moderate hepatic impairment (Child-Pugh B)
• Age ≥75 years
• Systolic blood pressure 100-110 mm Hg

Titration Schedule

• Double the dose every 2-4 weeks as tolerated 1
• Target maintenance dose: 97/103 mg twice daily 1, 2
• Minimum effective dose: 49/51 mg twice daily (50% of target dose meets quality metrics) 1

Monitoring Requirements

Initial Monitoring (Within 1-2 Weeks of Initiation or Dose Increase)

• Blood pressure (assess for symptomatic and asymptomatic hypotension) 3
• Serum creatinine and eGFR (monitor for worsening renal function) 1, 3
• Serum potassium (risk of hyperkalemia, especially with concurrent MRA) 1, 3

Ongoing Monitoring

• Serial assessments of blood pressure, renal function, and electrolytes at each dose titration 3
• Clinical symptoms of heart failure, functional capacity, and quality of life 1

Managing Common Adverse Effects

Hypotension (Most Common Side Effect)

Asymptomatic hypotension (SBP 90-100 mm Hg): Do not reduce or discontinue sacubitril/valsartan, as efficacy and safety are maintained even with baseline SBP <110 mm Hg. 4, 3

Symptomatic hypotension: 4, 3

1. Address reversible non-HF causes (dehydration, infection, arrhythmia)
2. Reduce or discontinue non-essential antihypertensives
3. Reduce loop diuretic dose in non-congested patients (sacubitril/valsartan enhances natriuresis)
4. Temporarily reduce sacubitril/valsartan dose only if above measures fail
5. Re-attempt uptitration once blood pressure stabilizes

Hyperkalemia

• More common with concurrent mineralocorticoid receptor antagonist use 1
• Manage with dietary potassium restriction, potassium-binding agents, or MRA dose reduction 1
• Do not routinely discontinue sacubitril/valsartan for mild hyperkalemia (K 5.3-5.5 mmol/L)

Worsening Renal Function

• Less common than with enalapril in PARADIGM-HF 1
• Symptomatic hypotension with sacubitril/valsartan was not associated with worsening renal function 1
• Temporary dose reduction or brief interruption may be needed for acute kidney injury

Angioedema

• Numerically higher but not statistically different from enalapril 1
• Absolute contraindication: History of angioedema with prior ACE inhibitor or ARB 1, 2
• Discontinue immediately if angioedema occurs

Absolute Contraindications

• Concomitant use with ACE inhibitors (Class III harm recommendation) 1, 2
• History of angioedema related to previous ACE inhibitor or ARB therapy 1, 2
• Concomitant use with aliskiren in patients with diabetes 2
• Pregnancy (causes fetal toxicity; discontinue immediately if pregnancy detected) 2
• Severe hepatic impairment (Child-Pugh C) 2, 5

Clinical Pitfalls to Avoid

Do not delay initiation waiting for aldosterone antagonist: Established use of an MRA is not mandatory before starting sacubitril/valsartan. 1

Do not withhold due to borderline blood pressure: Patients with SBP 100-110 mm Hg benefit equally; start at reduced dose (24/26 mg twice daily) and monitor closely. 4, 3

Do not stop at suboptimal doses: Aim for target dose (97/103 mg twice daily) or at minimum 50% of target dose (49/51 mg twice daily), as dose-response relationship exists for improved outcomes. 1

Do not forget the 36-hour washout from ACE inhibitors: This is the most critical safety step to prevent life-threatening angioedema. 1, 2

Place in Modern HFrEF Therapy

Sacubitril/valsartan is one of four foundational therapies (quadruple therapy) for HFrEF, alongside: 4

• Beta-blocker (carvedilol, metoprolol succinate, or bisoprolol)
• Mineralocorticoid receptor antagonist (spironolactone or eplerenone)
• SGLT2 inhibitor (dapagliflozin or empagliflozin)

This quadruple therapy provides approximately 73% mortality reduction over 2 years and 5.3 additional life-years compared to no treatment. 4