What is the recommended treatment and dosage for patients with heart failure with reduced ejection fraction using Entresto (sacubitril/valsartan)?

Entresto (Sacubitril/Valsartan) for Heart Failure with Reduced Ejection Fraction

Indication and Role in Treatment

Entresto is indicated for patients with heart failure with reduced ejection fraction (HFrEF) and NYHA class II-IV symptoms to reduce cardiovascular death and hospitalization, and should replace ACE inhibitors or ARBs as the preferred renin-angiotensin system inhibitor in symptomatic patients. 1, 2, 3

• The European Society of Cardiology recommends sacubitril/valsartan as superior to ACE inhibitors, providing at least 20% mortality reduction in symptomatic HFrEF patients 2
• Benefits are most clearly evident in patients with left ventricular ejection fraction below normal 3

Dosing Strategy

Standard Starting Dose

• Start at 49/51 mg orally twice daily for most patients 1, 3
• Double the dose every 2-4 weeks to reach the target maintenance dose of 97/103 mg twice daily, as tolerated 1, 3

Reduced Starting Dose (24/26 mg twice daily)

Use the lower starting dose in these specific situations 1, 3:

• Patients not currently taking an ACE inhibitor or ARB
• Patients previously on low doses of ACE inhibitors or ARBs
• Severe renal impairment
• Moderate hepatic impairment (Child-Pugh B) 1
• Elderly patients ≥75 years 1
• Patients with borderline blood pressure (systolic BP ≤100 mm Hg) 1

Critical Transition Requirements

ACE Inhibitor Washout

• A mandatory 36-hour washout period is required when switching from an ACE inhibitor to prevent angioedema 1, 4, 3
• Concomitant use with ACE inhibitors is absolutely contraindicated 1, 4, 3

ARB Transition

• No washout period is required when switching from an ARB 1

Titration and Monitoring

Titration Schedule

• The European Society of Cardiology recommends doubling the dose every 2-4 weeks as tolerated to reach the target dose of 97/103 mg twice daily 1
• Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 2

Monitoring Parameters

• Check renal function and electrolytes within 1-2 weeks after initiation and with each dose increase 4
• Monitor blood pressure closely, especially during initiation and dose titration 4
• Monitor for symptomatic hypotension, particularly during initiation and dose titration 1

Managing Hypotension

• Do not withhold therapy for asymptomatic low blood pressure with adequate perfusion 2
• If hypotension occurs, consider temporary dose reduction rather than discontinuation, as 40% of patients who required temporary dose reduction were subsequently restored to target doses 1, 4
• Consider reducing diuretic doses in non-congested patients to mitigate hypotensive effects 1
• Diuretic requirements may decrease due to enhanced natriuresis with Entresto 4

Concomitant Medications

Continue These Medications

• Beta-blockers (carvedilol, metoprolol succinate, or bisoprolol) must be continued as they are cornerstone therapy 2, 4
• Mineralocorticoid receptor antagonists (spironolactone or eplerenone) should be continued 1, 2
• SGLT2 inhibitors (dapagliflozin or empagliflozin) should be part of the treatment regimen 1, 2

Statin Interactions

• The American Heart Association recommends considering lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin when used with sacubitril/valsartan due to increased statin levels 1, 4

Common Pitfalls to Avoid

• Do not fail to observe the 36-hour ACE inhibitor washout period 4, 3
• Do not underdose due to concerns about renal function—while starting at a lower dose is appropriate, attempt to titrate to maximum tolerated dose as benefits are dose-dependent 4
• Do not discontinue therapy prematurely due to mild laboratory changes or asymptomatic hypotension 1, 4
• Do not fail to titrate to target doses due to asymptomatic hypotension or mild laboratory changes 1
• Do not permanently reduce doses when temporary reductions with subsequent re-titration would be more appropriate 1
• Do not accept suboptimal doses without attempting titration 2

Special Populations

Renal Impairment

• Severe renal impairment requires starting with 24/26 mg twice daily, not avoidance of therapy 1, 4
• Sacubitril/valsartan improves left ventricular systolic and diastolic function even in patients with end-stage kidney disease 5

History of Angioedema

• History of angioedema related to previous ACE inhibitor or ARB therapy is a precaution for Entresto use 1

Direct Initiation

• Recent data from the American College of Cardiology support direct initiation of sacubitril/valsartan without a pretreatment period with ACE inhibitors or ARBs as a safe and effective strategy 1

Expected Benefits

• Sacubitril/valsartan decreases prognostic biomarkers, improves health status, and reverses cardiac remodeling processes regardless of heart failure duration 6
• Improvements in conduit vessel function, functional capacity, and reduction in inflammation occur within 1-3 months of treatment 7