How to initiate a trial of low-dose Entresto (sacubitril/valsartan) in a patient with heart failure with reduced ejection fraction (HFrEF)?

How to Trial Low-Dose Entresto for a Heart Failure Patient

Start Entresto at 24/26 mg twice daily in patients with severe renal impairment (eGFR <30), moderate hepatic impairment, age ≥75 years, or borderline blood pressure (systolic BP ≤100 mmHg), then uptitrate every 2-4 weeks to the target dose of 97/103 mg twice daily unless clinically meaningful adverse events occur that persist despite adjusting other medications. 1, 2

Pre-Initiation Requirements

Before starting Entresto, verify the following contraindications are absent:

• History of angioedema related to previous ACE inhibitor or ARB therapy 2
• Current ACE inhibitor use - requires a mandatory 36-hour washout period to avoid angioedema 1, 2
• Pregnancy or lactation 2
• Severe hepatic impairment 2
• Concomitant aliskiren use in patients with diabetes 2

No washout period is required when switching from an ARB - you can start Entresto immediately 1

Starting Dose Selection Algorithm

Choose your starting dose based on these specific criteria:

24/26 mg twice daily for patients with ANY of the following: 1, 2

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Moderate hepatic impairment (Child-Pugh B)
• Age ≥75 years
• Systolic blood pressure ≤100 mmHg
• No prior ACE inhibitor or ARB exposure (de novo patients)
• Prior low/medium-dose ACE inhibitor or ARB

49/51 mg twice daily for patients with: 1

• Prior high-dose ACE inhibitor use
• None of the above risk factors

Uptitration Protocol

The forced-titration strategy used in landmark trials is essential - this is what demonstrated mortality benefit, not the starting dose 3. In PARADIGM-HF, few patients remained on 24/26 mg long-term, and >70% achieved target doses 3.

Titration Schedule:

• Double the dose every 2-4 weeks as tolerated 3, 1
• Target dose is 97/103 mg twice daily for all patients 3, 1
• Asymptomatic hypotension or mild laboratory changes should NOT prevent uptitration 3, 1

Monitoring During Titration:

Check within 1-2 weeks after each dose increase: 1

• Blood pressure (symptomatic hypotension only requires intervention)
• Renal function (mild creatinine elevation <0.5 mg/dL is acceptable)
• Potassium levels (especially with concurrent MRA use)

Managing Common Barriers to Uptitration

Critical pitfall: In clinical practice, <25% of patients ever reach target doses, yet subtarget doses have not been proven to prolong life 3. Avoid this by following these strategies:

Hypotension Management:

• Asymptomatic hypotension is NOT a reason to stop uptitration - Entresto maintains efficacy even with systolic BP <110 mmHg 1
• If symptomatic hypotension occurs: 1
  1. First reduce diuretic dose in non-congested patients
  2. If persistent, temporarily reduce Entresto dose
  3. Re-attempt uptitration - 40% of patients in PARADIGM-HF who required temporary dose reduction were successfully restored to target doses 3, 1

Renal Function Changes:

• Mild creatinine elevation (<0.5 mg/dL) does not require dose adjustment 1
• Continue monitoring but proceed with uptitration unless severe worsening occurs 1

Hyperkalemia:

• Monitor closely, especially with concurrent MRA use 1, 2
• Adjust MRA dose before reducing Entresto if possible 1

Concomitant Medication Adjustments

Reduce diuretic doses when initiating Entresto due to enhanced natriuresis 1

Consider lower statin doses - Entresto increases levels of statins that are OATP1B1, OATP1B3, OAT1, and OAT3 substrates (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) 1

Evidence Supporting This Approach

The mortality benefit of Entresto requires target dosing - the 20% reduction in cardiovascular death or HF hospitalization seen in PARADIGM-HF was achieved with 97/103 mg twice daily 3. The widespread practice of maintaining patients on starting doses indefinitely is not evidence-based and represents a critical gap in care 3.

Benefits occur regardless of heart failure duration - improvements in biomarkers, health status, and cardiac remodeling occur whether HF duration is <12 months or >60 months 4. This means you should not delay initiation based on disease chronicity.

Higher doses provide greater NT-proBNP reduction - a 2025 meta-analysis showed high-dose Entresto significantly reduced NT-proBNP levels (-667.24,95% CI: -1312.69 to -21.8; p=0.04) compared to low doses, indicating improved cardiac stress 5.

Special Population Considerations

NYHA Class IV patients: Entresto remains indicated but requires careful monitoring - 18% of patients in the LIFE trial could not tolerate even 100 mg/day during run-in, and 29% discontinued during 24 weeks 6. Start at 24/26 mg twice daily and uptitrate cautiously 1.

Recent hospitalization: Resolution of acute pulmonary congestion is required before initiation 1. Once hemodynamically stable, initiate Entresto before discharge to improve adherence 3.