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

Indications and Positioning in Treatment Algorithm

Entresto (sacubitril/valsartan) is the preferred first-line renin-angiotensin system inhibitor for symptomatic HFrEF patients, providing superior mortality reduction of at least 20% compared to ACE inhibitors. 1

• The European Society of Cardiology recommends sacubitril/valsartan as a replacement for ACE inhibitors to further reduce the risk of heart failure hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACE inhibitor, beta-blocker, and mineralocorticoid receptor antagonist. 2
• Entresto is FDA-approved to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure, with benefits most clearly evident in patients with LVEF below normal. 3
• The medication should be initiated as part of four foundational medication classes (ARNI/ACEi/ARB, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors) as soon as possible after diagnosis. 1

Dosing for Adults with HFrEF

The standard starting dose is 49/51 mg twice daily, with titration to the target maintenance dose of 97/103 mg twice daily after 2-4 weeks. 3

Standard Dosing Protocol:

• Starting dose: 49/51 mg orally twice daily for patients previously on high-dose ACE inhibitors. 2, 3
• Titration schedule: Double the dose every 2-4 weeks as tolerated to reach the target dose of 97/103 mg twice daily. 2, 3
• Target dose: 97/103 mg twice daily provides maximum mortality benefit. 2

Modified Starting Doses for Specific Populations:

• Patients not on ACE inhibitor/ARB or on low doses: Start at 24/26 mg twice daily (half the usual starting dose), then increase every 2-4 weeks. 2, 3
• Severe renal impairment: Start at 24/26 mg twice daily. 2, 3
• Moderate hepatic impairment (Child-Pugh B): Start at 24/26 mg twice daily. 2
• Elderly patients (≥75 years): Start at 24/26 mg twice daily. 2, 3
• Low blood pressure (systolic BP ≤100 mm Hg): Consider starting at 24/26 mg twice daily with slow up-titration. 2

Critical Safety Requirements

A mandatory 36-hour washout period must be observed when switching from an ACE inhibitor to Entresto to avoid angioedema. 2, 3

• Concomitant use with ACE inhibitors is contraindicated. 3
• No washout period is required when switching from an ARB to Entresto. 2
• History of angioedema related to previous ACE inhibitor or ARB therapy requires caution. 2
• Recent data support direct initiation of sacubitril/valsartan without pretreatment with ACEIs or ARBs as a safe and effective strategy. 2

Monitoring and Management of Side Effects

Monitor for symptomatic hypotension, especially during initiation and dose titration, and consider reducing diuretic doses in non-congested patients. 2

• Symptomatic hypotension in chronic HFrEF can usually be managed through patient education and counseling without reducing HF pharmacotherapy. 2
• For patients experiencing hypotension, consider temporarily reducing the dose rather than discontinuing therapy completely, as 40% of patients who required temporary dose reduction were subsequently restored to target doses. 2
• Monitor renal function and electrolytes, particularly when used with aldosterone antagonists. 2
• Sacubitril/valsartan may increase levels of statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters; consider lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin. 2

Common Pitfalls to Avoid

Do not fail to titrate to target doses due to asymptomatic hypotension or mild laboratory changes. 2

• Avoid permanent dose reductions when temporary reductions with subsequent re-titration would be more appropriate. 2
• Do not believe that medium-range doses provide most of the benefits of target doses—the target dose of 97/103 mg twice daily provides maximum mortality benefit. 2
• Real-world data shows that only 17% of patients achieved target dose after 4 months, with most remaining at the lowest dose—this represents suboptimal care. 4
• Diuretic doses may need to be reduced due to enhanced natriuresis when using sacubitril/valsartan. 2

Clinical Benefits and Evidence

Sacubitril/valsartan reduces the risk of heart failure hospitalization and death compared to ACE inhibitors in patients with symptomatic HFrEF despite optimal medical therapy. 2

• The medication demonstrates significant improvements in cardiac remodeling, with increased left ventricular ejection fraction and decreased left ventricular volumes. 2
• Real-world evidence shows reduction in all-cause inpatient stays from 27.5% pre-initiation to 17.0% post-initiation within 4 months. 4
• Improvements occur regardless of heart failure duration, with absolute LVEF improvements ranging from 6.9% to 12.2% across all duration categories. 5
• Benefits extend to patients with end-stage kidney disease, improving both systolic and diastolic function without increasing serum potassium. 6
• Emerging evidence suggests benefits in heart failure with mildly reduced ejection fraction (HFmrEF, LVEF 41-49%). 2

Initiation in Hospitalized Patients

Resolution of acute pulmonary congestion is required for hemodynamic stabilization before initiating sacubitril/valsartan in hospitalized patients. 2

• Continue mineralocorticoid receptor antagonists (spironolactone or eplerenone) as cornerstone therapy when initiating sacubitril/valsartan. 2