What is the role of Entresto (sacubitril/valsartan) in treating heart failure with reduced ejection fraction?

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

Entresto is a foundational therapy for HFrEF that should replace ACE inhibitors or ARBs in symptomatic patients to reduce cardiovascular death and heart failure hospitalization. 1

Primary Indication and Clinical Benefits

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. 1

• The drug combines sacubitril (a neprilysin inhibitor) with valsartan (an angiotensin II receptor blocker), providing dual mechanism benefits through enhanced natriuretic peptide availability and angiotensin receptor blockade. 1
• Real-world Italian data confirm that 56.3% of patients achieved ≥5% improvement in LVEF at one year, with 37.5% showing NYHA class improvement after mean 5.3 months of treatment. 2

Treatment Algorithm and Positioning

The 2022 ACC/AHA/HFSA guidelines recommend Entresto as part of guideline-directed medical therapy (GDMT) for HFrEF, with the European Society of Cardiology positioning it as third-line therapy after ACE inhibitor/beta-blocker and mineralocorticoid receptor antagonist. 3, 4

The treatment sequence is:

• First-line: ACE inhibitor + beta-blocker 4
• Second-line: Add mineralocorticoid receptor antagonist (MRA) if symptomatic 4
• Third-line: Replace ACE inhibitor/ARB with sacubitril/valsartan if still symptomatic 4
• Additional therapy: SGLT2 inhibitor (dapagliflozin or empagliflozin) to further reduce hospitalization and death 4

However, all HFrEF patients on ACE inhibitors or ARBs are candidates for switching to sacubitril/valsartan without needing to "fail" optimal medical therapy first. 4

Dosing and Titration Protocol

Start with 49/51 mg twice daily for patients previously on high-dose ACE inhibitors, or 24/26 mg twice daily for those on low/medium-dose ACE inhibitors, ARBs, or treatment-naïve patients. 4, 1

High-Risk Patients Requiring Lower Starting Dose (24/26 mg twice daily):

• Severe renal impairment (eGFR <30 mL/min/1.73 m²) 4
• Moderate hepatic impairment (Child-Pugh B) 4
• Elderly patients ≥75 years 4
• Systolic BP ≤100 mmHg 4

Double the dose every 2-4 weeks as tolerated to reach the target dose of 97/103 mg twice daily, which provides maximum mortality benefit. 4, 1

Critical Switching Requirements

When switching from an ACE inhibitor to Entresto, a mandatory 36-hour washout period must be observed to avoid angioedema. 4, 1

• No washout period is required when switching from an ARB. 4
• Concomitant use with ACE inhibitors is absolutely contraindicated. 4, 1

Managing Common Barriers and Adverse Effects

Hypotension Management:

Asymptomatic hypotension should not prevent Entresto initiation or uptitration, as the drug maintains efficacy and safety even in patients with systolic BP <110 mmHg. 4

• If symptomatic hypotension occurs, reduce diuretic dose first in non-congested patients. 4
• Consider temporarily reducing sacubitril/valsartan dose rather than discontinuing completely—40% of patients requiring temporary dose reduction were subsequently restored to target doses. 4
• Real-world data show 12% of patients experienced hypotension during follow-up, but this was manageable. 2

Renal Function:

• Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment. 4
• Monitor renal function and electrolytes, particularly when used with aldosterone antagonists. 4
• Real-world data show only 2.2% had hyperkalemia during characterization and 2.6% during follow-up. 2

Diuretic Adjustment:

Diuretic doses may need reduction due to enhanced natriuresis when using sacubitril/valsartan. 4

Special Populations and Considerations

Entresto remains indicated in patients with NYHA class IV symptoms, though data in this population are limited. 4

• Benefits occur regardless of heart failure duration, age, sex, or background medical therapy. 4
• The drug is effective in vulnerable populations including those with signs of congestion and recent heart failure hospitalization. 4
• Benefits occur within weeks of initiation. 4

Emerging Evidence in HFmrEF

Post-hoc analysis of PARAGON-HF suggests benefit of sacubitril/valsartan in patients with LVEF 45-57% (rate ratio 0.78; 95% CI 0.64-0.95). 3

• The 2022 ACC/AHA/HFSA guidelines give a Class 2b recommendation for ARNi use in symptomatic HF with LVEF 41-49%. 3
• A 2024 meta-analysis showed sacubitril/valsartan improved KCCQ CSS (mean difference 1.13), NYHA class (OR 1.32), and composite outcome of HF hospitalization/cardiovascular death (RR 0.86) compared to valsartan in HFmrEF/HFpEF patients. 5

Critical Pitfalls to Avoid

Do not fail to titrate to target doses due to asymptomatic hypotension or mild laboratory changes—target doses provide maximum benefit. 4

• Do not make permanent dose reductions when temporary reductions with subsequent re-titration would be more appropriate. 4
• Do not treat heart failure less aggressively than other life-threatening conditions despite similar mortality risks. 4
• Do not believe that medium-range doses provide most of the benefits of target doses—they do not. 4

Drug Interactions

Consider lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin when used with sacubitril/valsartan, as it may increase statin levels through OATP1B1, OATP1B3, OAT1, and OAT3 transporter inhibition. 4

Contraindications

Absolute contraindications include: 4, 1

• History of angioedema related to previous ACE inhibitor or ARB therapy
• Pregnancy or lactation (discontinue immediately when pregnancy detected)
• Severe hepatic impairment
• Concomitant ACE inhibitor use