Entresto (Sacubitril/Valsartan): Essential Clinical Information
What It Is and How It Works
Entresto is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that combines sacubitril (a neprilysin inhibitor) with valsartan (an ARB), providing dual mechanism therapy for heart failure. 1 The neprilysin inhibition increases circulating natriuretic peptides, producing natriuretic, diuretic, and vasodilatory effects, while valsartan blocks the angiotensin II receptor 2.
FDA-Approved Indications
- Adults with chronic heart failure with reduced ejection fraction (HFrEF) to reduce risk of cardiovascular death and hospitalization 1
- Children ≥1 year old with symptomatic heart failure due to systemic left ventricular systolic dysfunction 1
When to Use It (Based on 2022 Guidelines)
Patients with chronic stable HFrEF who tolerate ACE inhibitors or ARBs should be switched to Entresto. 3 The 2022 AHA/ACC/HFSA guidelines give this a Class 1 recommendation based on the PARADIGM-HF trial, which demonstrated significant reductions in hospitalizations and mortality compared to enalapril 4, 3.
Key Evidence
In PARADIGM-HF, patients with mild-to-moderate HF who tolerated target-dose enalapril (10 mg twice daily) and then Entresto (200 mg twice daily) had significantly decreased hospitalizations and mortality with the ARNI 3. Multiple cost-effectiveness analyses consistently found Entresto provides high value with costs per QALY <$60,000 3.
Dosing
Available strengths: 24/26 mg, 49/51 mg, and 97/103 mg (sacubitril/valsartan) 1
Standard dosing: Twice daily, with target maintenance dose of 97/103 mg twice daily 1
Start lower doses (24/26 mg twice daily) in patients with:
- Severe renal impairment
- Moderate hepatic impairment
- Low blood pressure 2
Pediatric dosing: Target maintenance dose is 3.1 mg/kg twice daily for children 1-18 years old 1
Critical Contraindications and Safety
Absolute Contraindications 1
- History of angioedema with ACE inhibitors or ARBs
- Concomitant ACE inhibitor use (requires 36-hour washout period when switching)
- Diabetes patients taking aliskiren
- Pregnancy (can cause fetal harm or death)
The 36-Hour Rule
You must wait 36 hours after stopping an ACE inhibitor before starting Entresto, and vice versa. 3, 1, 2 This is non-negotiable due to the risk of angioedema from dual neprilysin and ACE inhibition, as demonstrated by the failed omapatrilat trials which showed 3-fold increased angioedema risk 3.
Major Side Effects to Monitor
Hypotension: Most common dose-limiting side effect 4, 1. In PARAGON-HF, hypotension occurred more frequently with Entresto than valsartan 4. Monitor closely, especially during initiation and uptitration.
Angioedema: Risk of serious allergic reactions causing facial, lip, tongue, and throat swelling that may cause trouble breathing and death 1. Black patients and smokers are at particularly high risk based on omapatrilat data 3.
Hyperkalemia and renal dysfunction: Monitor potassium and renal function, though Entresto actually showed favorable effects on these parameters compared to valsartan in PARAGON-HF 4.
Newly recognized: Isolated elevation of PT/INR without anticoagulant use has been reported (Naranjo score +9), requiring periodic coagulation monitoring 5.
Drug Interactions 1
Avoid or use caution with:
- Potassium supplements or salt substitutes
- NSAIDs
- Lithium
- Other RAS blockers (ACE inhibitors, ARBs, aliskiren)
Special Populations
Heart Failure with Preserved Ejection Fraction (HFpEF)
The PARAGON-HF trial showed Entresto did not achieve statistical significance for the primary endpoint in HFpEF (LVEF ≥45%) 4. However, exploratory analyses suggested benefit in:
- Women (rate ratio 0.73)
- Patients with LVEF 45-57% (rate ratio 0.78) 4
The 2022 guidelines give this a Class 2b recommendation for HFpEF 4.
Hemodialysis Patients
Real-world data shows dose reduction or discontinuation is common in HD patients 6. Diabetes, higher NT-proBNP, and higher interdialytic weight gain predict intradialytic hypotension 6. Use with extreme caution and close monitoring.
Pregnancy and Breastfeeding
Absolutely contraindicated in pregnancy - can cause fetal harm or death 1. Discuss alternative treatments if pregnancy is planned. Do not breastfeed while taking Entresto 1.
Practical Implementation
Switching from ACE inhibitor/ARB:
- Stop ACE inhibitor
- Wait 36 hours minimum
- Start Entresto at appropriate dose based on patient factors
- Uptitrate as tolerated to target dose 2
Monitoring:
- Blood pressure (especially first few weeks)
- Renal function and potassium
- Consider periodic PT/INR monitoring 5
- Symptoms of angioedema
Storage
Store at 20-25°C (68-77°F), protect from moisture 1
Comparative Effectiveness
Recent real-world data suggests in patients WITHOUT diabetes, Entresto was associated with lower risks of HF-related hospitalization (aHR 0.65) and all-cause hospitalization (aHR 0.69) compared to SGLT2 inhibitors 7. However, in patients WITH diabetes, there was no significant difference between the two therapies 7. This provides important guidance for medication selection based on diabetes status.