How should I initiate sacubitril/valsartan (Entresto) in an adult with symptomatic heart failure with reduced ejection fraction (NYHA class II‑III, EF ≤40%) who is already on a stable ACE inhibitor, ARB, beta‑blocker, and mineralocorticoid receptor antagonist?

Initiating Sacubitril/Valsartan in Patients Already on ACE Inhibitors

Stop the ACE inhibitor immediately and observe a mandatory 36-hour washout period before starting sacubitril/valsartan to prevent life-threatening angioedema. 1, 2, 3

Pre-Initiation Checklist

Before switching, verify the patient meets these criteria:

• Systolic blood pressure ≥100 mm Hg is preferred, though lower BP is not an absolute contraindication if the patient is otherwise stable 1, 4
• eGFR >30 mL/min/1.73 m² for standard dosing; patients with eGFR ≤30 mL/min/1.73 m² have limited trial evidence but can be initiated with caution at reduced doses 1, 4
• No history of angioedema related to previous ACE inhibitor or ARB therapy (absolute contraindication) 3
• Not pregnant or breastfeeding (contraindicated due to fetal toxicity) 3
• No severe hepatic impairment (Child-Pugh C is contraindicated; Child-Pugh B requires dose adjustment) 3, 5
• Patient is hemodynamically stable and not volume-depleted or actively decompensated 1

Washout Period: Critical Safety Step

• Discontinue the ACE inhibitor and wait exactly 36 hours before administering the first dose of sacubitril/valsartan 1, 2, 3
• This washout period is non-negotiable to avoid the risk of angioedema from dual neprilysin and ACE inhibition 2, 3
• Continue all other heart failure medications (beta-blocker, mineralocorticoid receptor antagonist) during the washout period 4, 2

Initial Dosing Strategy

For patients previously on high-dose ACE inhibitors (equivalent to enalapril ≥10 mg daily):

• Start sacubitril/valsartan 49/51 mg twice daily 1, 4

For patients on low-to-medium dose ACE inhibitors (equivalent to enalapril <10 mg daily):

• Start sacubitril/valsartan 24/26 mg twice daily 1, 4

Special populations requiring the lower starting dose (24/26 mg twice daily):

• Severe renal impairment (eGFR <30 mL/min/1.73 m²) 1, 4, 3
• Moderate hepatic impairment (Child-Pugh B) 4, 3
• Age ≥75 years 4
• Systolic BP 100-110 mm Hg 1, 4

Titration Schedule

• Double the dose every 2-4 weeks as tolerated by the patient 1, 4
• Target dose is 97/103 mg twice daily, which provides maximum mortality benefit demonstrated in clinical trials 4, 6
• The dose progression is: 24/26 mg → 49/51 mg → 97/103 mg (all twice daily) 4

Managing Diuretics During Transition

• Consider empirically reducing loop diuretic doses in non-congested patients at the time of sacubitril/valsartan initiation to mitigate hypotensive effects 1, 4
• Sacubitril/valsartan enhances natriuresis, so diuretic requirements often decrease 4, 2
• This proactive diuretic reduction can prevent symptomatic hypotension while maintaining the patient's volume status 1

Monitoring Protocol

Within 1-2 weeks after initiation and with each dose increase, check:

• Blood pressure (watch for symptomatic hypotension) 4, 2
• Serum creatinine and eGFR 4, 2
• Serum potassium (especially important when combined with mineralocorticoid receptor antagonists) 4, 2

Ongoing monitoring:

• Continue routine monitoring of electrolytes and renal function, with frequency adjusted based on clinical status 4
• Particular vigilance is needed in patients with baseline renal impairment or those on aldosterone antagonists 4

Managing Common Barriers to Optimal Dosing

Asymptomatic hypotension:

• Do not reduce the dose or avoid uptitration for asymptomatic low blood pressure 4, 7
• Sacubitril/valsartan maintains efficacy and safety even with systolic BP <110 mm Hg 4, 7
• The mortality benefit persists regardless of baseline blood pressure 4, 7

Symptomatic hypotension:

• First, reduce loop diuretic doses in non-congested patients 1, 7
• If symptoms persist, temporarily reduce sacubitril/valsartan dose, then re-titrate upward once symptoms resolve 4, 7
• Approximately 40% of patients requiring temporary dose reduction can subsequently be restored to target doses 4, 2

Mild creatinine elevation (<0.5 mg/dL increase):

• This is acceptable and does not require dose adjustment or discontinuation 4, 7
• Continue monitoring but maintain the current dose 4

Hyperkalemia:

• Monitor potassium levels closely, especially when combined with mineralocorticoid receptor antagonists 4, 2
• Exercise caution when serum potassium >5.0 mEq/L 4
• Adjust concomitant medications (consider reducing or temporarily holding MRA) rather than discontinuing sacubitril/valsartan 7

Critical Pitfalls to Avoid

• Never co-administer sacubitril/valsartan with ACE inhibitors—this is an absolute contraindication 2, 3
• Do not skip or shorten the 36-hour washout period from ACE inhibitors 2, 3
• Do not underdose due to concerns about renal function or blood pressure—attempt to reach target doses as benefits are dose-dependent 4, 2
• Do not permanently reduce doses when temporary reduction with subsequent re-titration would be more appropriate 4
• Do not discontinue therapy prematurely due to mild laboratory changes or asymptomatic hypotension 2
• Do not fail to continue beta-blockers and mineralocorticoid receptor antagonists—these remain cornerstone therapies 4, 2

Evidence Base and Rationale

• The PARADIGM-HF trial demonstrated that sacubitril/valsartan reduces cardiovascular death or heart failure hospitalization by 20% compared to enalapril in patients with chronic HFrEF 4, 6, 8
• This mortality benefit is maintained across all NYHA classes (II-IV), though the strongest evidence exists for NYHA class II patients who comprised 70.5% of the trial population 1
• Recent evidence supports that direct initiation without prior ACE inhibitor exposure is safe and effective, but in your patient already on an ACE inhibitor, the 36-hour washout remains mandatory 1, 4
• The European Society of Cardiology and American College of Cardiology both recommend sacubitril/valsartan as a replacement for ACE inhibitors in symptomatic HFrEF patients despite optimal therapy 1, 4

Drug Interactions to Consider

• Statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters may have increased levels when combined with sacubitril/valsartan 4
• Consider lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin 4