In an adult with symptomatic chronic heart failure with reduced ejection fraction (NYHA class II‑IV) already receiving a beta‑blocker and a mineralocorticoid receptor antagonist, when is Entresto (sacubitril/valsartan) indicated, what are the appropriate starting and target doses, contraindications, and required monitoring?

Entresto (Sacubitril/Valsartan) in HFrEF: Indications, Dosing, and Monitoring

When to Initiate Entresto

Entresto is indicated for adults with symptomatic chronic heart failure (NYHA class II-IV) and reduced ejection fraction (≤40%) who remain symptomatic despite treatment with an ACE inhibitor or ARB, beta-blocker, and mineralocorticoid receptor antagonist. 1, 2

Prerequisite Requirements Before Starting

• Confirm the patient has achieved target or maximally tolerated doses of ACE inhibitor/ARB, evidence-based beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), and MRA for a meaningful duration 1
• Verify systolic blood pressure >100 mmHg at the time of initiation 2
• Confirm eGFR >30 mL/min/1.73 m² 2
• Check serum potassium <5.2 mmol/L before starting 2
• Document persistent symptoms (NYHA class II or higher) despite optimal medical therapy 1, 3

Critical Timing Consideration

Do not switch asymptomatic patients (NYHA class I) from ACE inhibitor to Entresto solely based on low ejection fraction—symptom status is the primary determinant for initiating therapy. 2 The PARADIGM-HF trial that established Entresto's efficacy enrolled 70.1% NYHA II, 23.9% NYHA III, and 0.7% NYHA IV patients; NYHA I patients were not studied. 2

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Dosing Protocol

Starting Dose

Begin with sacubitril 49 mg/valsartan 51 mg twice daily in most patients. 1

Use a reduced starting dose (sacubitril 24 mg/valsartan 26 mg twice daily) if: 1

• Not currently on an ACE inhibitor/ARB or taking low doses
• Severe renal impairment (eGFR 30-60 mL/min/1.73 m²)
• Moderate hepatic impairment
• Systolic blood pressure 100-110 mmHg

Target Dose

Uptitrate to sacubitril 97 mg/valsartan 103 mg twice daily over 4-8 weeks using 2-week intervals between dose increases. 1, 2 This target dose provides at least 20% mortality reduction superior to ACE inhibitors. 1, 2

Mandatory Washout Period

Discontinue ACE inhibitor 36 hours before starting Entresto to prevent angioedema. 1 Never combine Entresto with an ACE inhibitor. 2

Dose Achieved in Clinical Trials

The mean dose achieved in PARADIGM-HF was sacubitril 182 mg/valsartan 193 mg total daily (equivalent to 91/96.5 mg twice daily). 1 Aggressive uptitration to target doses using a forced-titration strategy is essential—clinical trials demonstrated benefits at target doses, not low doses. 1

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Absolute Contraindications

• History of angioedema related to previous ACE inhibitor or ARB therapy 1
• Concomitant use with ACE inhibitors (36-hour washout required) 1, 2
• Concomitant use with aliskiren in patients with diabetes 1
• Pregnancy (discontinue immediately if pregnancy detected) 1
• Severe hepatic impairment (Child-Pugh C) 1

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Monitoring Requirements

Initial Monitoring (First 3 Months)

Check blood pressure, renal function (serum creatinine, eGFR), and serum potassium at:

• Baseline before initiation 4, 5
• 1-2 weeks after each dose increment 1, 2
• 3 months after reaching target dose 4

Long-Term Monitoring

Reassess blood pressure, renal function, and electrolytes every 6 months once stable on target dose. 4, 5

Managing Common Monitoring Findings

Hypotension (SBP <100 mmHg):

• If asymptomatic with adequate perfusion, do not reduce Entresto dose 2
• Address reversible non-HF causes first: stop alpha-blockers (tamsulosin, doxazosin), discontinue other non-essential BP-lowering medications, evaluate for dehydration or infection 2
• Consider reducing diuretic dose if patient is euvolemic 2
• Only if symptomatic hypotension persists after above steps, temporarily reduce Entresto dose 2

Hyperkalemia (K+ 5.2-5.5 mmol/L):

• Reduce or stop potassium supplements and potassium-sparing diuretics 1
• Consider potassium binders (patiromer, sodium zirconium cyclosilicate) rather than discontinuing life-saving medications 2
• Entresto actually reduces hyperkalemia risk compared to ACE inhibitor plus MRA 2

Worsening Renal Function (Creatinine increase up to 30% above baseline):

• This is acceptable and should not prompt discontinuation 2
• Interpret kidney function changes in the context of decongestion—worsening kidney function with successful decongestion is associated with lower mortality than failure to decongest with stable kidney function 2

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Critical Pitfalls to Avoid

• Delaying initiation in symptomatic patients who meet criteria while waiting to "optimize" other medications indefinitely 1
• Accepting suboptimal doses due to unfounded blood pressure concerns—GDMT maintains efficacy even with baseline SBP <110 mmHg 2
• Discontinuing therapy for asymptomatic hypotension—adverse events occur in 75-85% of HFrEF patients regardless of treatment, with no substantial difference between GDMT and placebo 2
• Switching asymptomatic patients (NYHA I) from ACE inhibitor to Entresto without documented symptoms 2
• Failing to use forced-titration strategy—uptitrate every 2 weeks unless clinically meaningful adverse events occur 1
• Using non-evidence-based beta-blockers (metoprolol tartrate, atenolol) instead of carvedilol, metoprolol succinate, or bisoprolol 1, 2

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Integration with Other HFrEF Therapies

Entresto should be combined with:

• SGLT2 inhibitor (dapagliflozin 10 mg or empagliflozin 10 mg once daily)—start immediately, minimal BP effect 2, 5
• Mineralocorticoid receptor antagonist (spironolactone 25-50 mg or eplerenone 50 mg daily)—provides 30% mortality reduction 1, 2
• Evidence-based beta-blocker (carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, or bisoprolol 10 mg daily)—provides 34% mortality reduction 1, 2
• Loop diuretics as needed for volume management 1, 5

This quadruple therapy provides approximately 61% reduction in all-cause mortality (HR 0.39,95% CI: 0.32-0.49) and 5.3 additional life-years compared to no treatment. 2