What is the recommended starting dose and dosing frequency of sacubitril/valsartan (Entresto) for a patient with chronic heart failure with reduced ejection fraction who is already on optimal background therapy (beta‑blocker, mineralocorticoid receptor antagonist, diuretic as needed) and has no contraindications to neprilysin inhibition?

Sacubitril/Valsartan Dosing for Heart Failure with Reduced Ejection Fraction

Recommended Starting Dose and Frequency

Start sacubitril/valsartan at 49/51 mg orally twice daily, then double the dose after 2-4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated. 1, 2

Standard Initiation Protocol

• The standard starting dose is 49/51 mg twice daily for most patients already on optimal background therapy (beta-blocker, mineralocorticoid receptor antagonist, diuretics) 1, 2

• Uptitrate to the target dose of 97/103 mg twice daily after 2-4 weeks if the initial dose is tolerated 1, 2

• The dosing frequency is always twice daily (BID), regardless of dose strength 1, 2

Modified Starting Dose for Specific Populations

Use the lower starting dose of 24/26 mg twice daily in patients with:

• Severe renal impairment (eGFR <30 mL/min/1.73 m²) 2
• Moderate hepatic impairment 2, 3
• Systolic blood pressure <100 mmHg 2, 3
• Patients not currently taking an ACE inhibitor or ARB, or previously on low doses of these agents 1, 2

For these patients, uptitrate every 2-4 weeks following the sequence: 24/26 mg BID → 49/51 mg BID → 97/103 mg BID 1, 2

Critical Washout Period

Allow a mandatory 36-hour washout period between discontinuing an ACE inhibitor and starting sacubitril/valsartan to minimize angioedema risk 1, 2, 3

• Patients can switch directly from an ARB to sacubitril/valsartan without a washout period 2

Titration Strategy and Monitoring

Increase the dose every 2-4 weeks as tolerated, monitoring blood pressure, renal function (creatinine), and potassium at each titration step 1

• The goal is to achieve the target dose of 97/103 mg twice daily, which was the dose used in the PARADIGM-HF trial that demonstrated a 16-20% reduction in cardiovascular mortality 1, 4

• In the pivotal PARADIGM-HF trial, over 70% of patients achieved and maintained the target dose of 97/103 mg twice daily 1

• Asymptomatic hypotension does not require dose reduction unless systolic blood pressure falls below 90 mmHg with symptoms 1

Managing Barriers to Target Dosing

If hypotension occurs during titration:

• First reduce or discontinue nitrates, calcium channel blockers, or other vasodilators 1
• If no signs of congestion are present, reduce loop diuretic dose to facilitate further uptitration 1
• Consider temporarily reducing the sacubitril/valsartan dose, then attempt re-escalation after 1-2 weeks 1

If renal function worsens:

• Small increases in creatinine (up to 30% above baseline) are acceptable and do not require dose adjustment 1
• Seek specialist consultation if creatinine exceeds 2.5 mg/dL (221 μmol/L) 1

If hyperkalemia develops (K+ >5.0 mmol/L):

• Discontinue potassium supplements and potassium-sparing diuretics first 1
• Consider reducing or temporarily holding the mineralocorticoid receptor antagonist 1
• Seek specialist advice for persistent hyperkalemia 1

Integration with Other Guideline-Directed Medical Therapy

Sacubitril/valsartan should be part of comprehensive quadruple therapy that includes a beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor 1, 5

• It is not necessary to achieve target doses of beta-blockers or mineralocorticoid receptor antagonists before initiating or uptitrating sacubitril/valsartan 1

• Evidence from PARADIGM-HF demonstrates that sacubitril/valsartan does not lead to greater discontinuation of beta-blockers or mineralocorticoid receptor antagonists compared to enalapril 6

• In fact, sacubitril/valsartan was associated with fewer discontinuations of mineralocorticoid receptor antagonists (6.2% vs 9.0%) compared to enalapril at 12 months 6

Common Pitfall to Avoid

The most common error in clinical practice is initiating sacubitril/valsartan at 24/26 mg twice daily and failing to uptitrate to target doses 1

• In real-world practice, fewer than 25% of patients are ever titrated to the target dose of 97/103 mg twice daily, despite evidence that over 70% can achieve this dose 1

• Low starting doses have not been proven to reduce mortality—only the target doses used in clinical trials have demonstrated survival benefit 1

• When dose reductions occur in clinical trials, 40% of patients are successfully restored to target doses, whereas in clinical practice, dose reductions are typically permanent 1

Expected Clinical Benefits at Target Dose

At the target dose of 97/103 mg twice daily, sacubitril/valsartan provides:

• 16-20% relative reduction in all-cause mortality compared to enalapril 1, 4
• 21% relative reduction in cardiovascular death or heart failure hospitalization 4
• Number needed to treat of 27 to prevent one death over 36 months 1