Can Entresto (sacubitril/valsartan) help with heart failure, specifically heart failure with reduced ejection fraction (HFrEF)?

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

Yes, Entresto is highly effective for heart failure with reduced ejection fraction (HFrEF) and is FDA-approved to reduce the risk of cardiovascular death and hospitalization in adult patients with chronic HFrEF. 1

Primary Indication and Evidence Base

Entresto should replace ACE inhibitors or ARBs in symptomatic HFrEF patients to further reduce mortality and hospitalization risk. 2 The drug demonstrated a 20% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization compared to enalapril in the PARADIGM-HF trial. 2

When to Initiate Entresto

Start Entresto in HFrEF patients (LVEF ≤40%) who remain symptomatic (NYHA class II-IV) despite optimal medical therapy with an ACE inhibitor, beta-blocker, and mineralocorticoid receptor antagonist. 2, 1 However, recent evidence supports direct initiation without requiring patients to "fail" prior therapy first. 2

Treatment Algorithm Position:

• First-line: ACE inhibitor + beta-blocker 2
• Second-line: Add mineralocorticoid receptor antagonist if symptomatic 2
• Third-line: Replace ACE inhibitor/ARB with sacubitril/valsartan if still symptomatic 2
• Concurrent: Add SGLT2 inhibitor (dapagliflozin or empagliflozin) to reduce hospitalization and death 2

Dosing and Titration Strategy

Starting Dose:

• Standard patients: 49/51 mg twice daily 2, 1
• High-risk patients (severe renal impairment with eGFR <30 mL/min/1.73 m², moderate hepatic impairment, or age ≥75 years): 24/26 mg twice daily 2, 1

Titration Schedule:

Double the dose every 2-4 weeks as tolerated, targeting 97/103 mg twice daily for maximum mortality benefit. 2, 1 This target dose provides superior outcomes compared to medium-range doses. 2

Critical Safety Requirements

ACE Inhibitor Washout:

A mandatory 36-hour washout period is required when switching from an ACE inhibitor to Entresto to prevent angioedema. 2, 1 No washout is needed when switching from an ARB. 2

Contraindications:

• History of angioedema related to previous ACE inhibitor or ARB therapy 1
• Concomitant use with ACE inhibitors 1
• Concomitant use with aliskiren in patients with diabetes 1
• Pregnancy (causes fetal toxicity) 1

Managing Common Barriers to Therapy

Hypotension:

Asymptomatic hypotension should not prevent Entresto initiation or uptitration, as the drug maintains efficacy and safety regardless of baseline blood pressure, even in patients with systolic BP <110 mmHg. 3, 2 In PARADIGM-HF, patients with baseline SBP 95-110 mmHg experienced only a -1.50 mmHg decrease with treatment, which diminished to <1 mmHg after 4 months. 3

If symptomatic hypotension occurs:

1. Reduce diuretic dose first in non-congested patients 2
2. If needed, temporarily reduce Entresto dose rather than discontinuing 2
3. Re-titrate upward once tolerated, as 40% of patients requiring temporary dose reduction were successfully restored to target doses 2

Blood Pressure Considerations:

Patients with systolic BP ≥100 mmHg are preferred candidates, but lower BP is not an absolute contraindication. 3, 2 Monitor closely during initiation and dose titration in patients with borderline blood pressure. 2

Renal Function:

Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment. 2 Monitor renal function and electrolytes within 1-2 weeks after initiation and with each dose increase. 2, 1

Clinical Benefits Across Disease Duration

Entresto provides consistent benefits regardless of heart failure duration, with significant improvements in biomarkers (NT-proBNP, troponin T, ST2), health status scores, and reverse cardiac remodeling occurring whether HF duration is <12 months or >60 months. 4 Absolute LVEF improvements ranged from 6.9% to 12.2% across all duration categories. 4

Efficacy in Special Populations

The drug maintains effectiveness in vulnerable populations including those with signs of congestion, recent heart failure hospitalization, and elderly patients. 3 Benefits occur within weeks of initiation and are independent of age, sex, or background medical therapy. 3

Potential Drug Interactions

Consider lower doses of statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) when used with Entresto, as it may increase statin levels through OATP1B1, OATP1B3, OAT1, and OAT3 transporter inhibition. 2

Common Prescribing Pitfalls to Avoid

• Do not wait for patients to "fail" optimal medical therapy before initiating Entresto—consider it proactively in symptomatic HFrEF patients 2
• Do not permanently reduce doses due to asymptomatic hypotension or mild laboratory changes when temporary reduction with re-titration is more appropriate 2
• Do not accept medium-range doses as adequate—target the full 97/103 mg twice daily dose for maximum benefit 2
• Do not forget the 36-hour ACE inhibitor washout period 2, 1
• Do not discontinue therapy for asymptomatic hypotension, which can usually be managed through patient education without reducing heart failure pharmacotherapy 3, 2