What is the recommended use of Angiotensin-Receptor Neprilysin Inhibitors (ARNI) such as sacubitril/valsartan (Sacubitril/Valsartan) in a hospital setting for patients with heart failure with reduced ejection fraction?

ARNI Initiation in Hospitalized Heart Failure Patients

Sacubitril/valsartan can and should be initiated during hospitalization for acute decompensated heart failure after hemodynamic stabilization, as this approach is both safe and effective, with no increased risk of adverse events compared to delayed initiation. 1

Evidence Supporting In-Hospital Initiation

The PIONEER-HF trial definitively established that starting sacubitril/valsartan in the hospital setting after hemodynamic stabilization leads to:

• Greater reduction in NT-proBNP (46.7% vs 25.3% with enalapril) as early as week 1, indicating superior neurohormonal modulation 1
• No difference in safety outcomes including worsening renal function, hyperkalemia, symptomatic hypotension, or angioedema compared to enalapril 1
• Approximately 25% incidence of hypotension, which is manageable and should not prevent initiation 2

When to Initiate During Hospitalization

Timing is critical: Only start sacubitril/valsartan after achieving hemodynamic stabilization, defined as:

• Resolution of acute pulmonary congestion
• Stable blood pressure (though benefits are maintained even with systolic BP <110 mmHg) 2
• No requirement for intravenous vasodilators or inotropes
• Stable renal function 1

Practical Implementation Protocol

Step 1: Pre-Initiation Requirements

• Mandatory 36-hour washout if switching from an ACE inhibitor (lisinopril, enalapril, etc.) to avoid angioedema 3, 4, 5
• No washout needed when switching from an ARB 3
• Ensure patient is not volume-depleted to minimize hypotension risk 2

Step 2: Starting Dose Selection

Choose initial dose based on patient characteristics 6, 4:

• 49/51 mg twice daily: Standard starting dose for most patients previously on high-dose ACE inhibitors 6
• 24/26 mg twice daily: Use for patients with:
  • Low/medium-dose ACE inhibitor or ARB exposure 6
  • Severe renal impairment 3, 4
  • Moderate hepatic impairment (Child-Pugh B) 6, 4
  • Age ≥75 years 6
  • Borderline blood pressure (systolic BP ≤100 mmHg) 6

Step 3: Titration Strategy

• Double the dose every 2-4 weeks as tolerated 6, 4
• Target dose: 97/103 mg twice daily for maximum mortality benefit 6, 4
• If hypotension occurs, consider temporary dose reduction rather than discontinuation—40% of patients requiring temporary reduction can be restored to target doses 6, 2

Managing Common In-Hospital Concerns

Hypotension Management

• Reduce diuretic doses in non-congested patients rather than stopping sacubitril/valsartan 6, 2
• Provide patient education about asymptomatic hypotension (16% incidence), which does not require intervention 2
• Symptomatic hypotension (11% incidence) can usually be managed without reducing heart failure therapy 6

Monitoring Requirements

Check within 1-2 weeks after initiation and with each dose increase 3:

• Blood pressure
• Renal function (serum creatinine, eGFR)
• Electrolytes (particularly potassium)

Critical Contraindications

Absolute contraindications 4:

• Concomitant ACE inhibitor use (requires 36-hour washout)
• History of angioedema with prior ACE inhibitor or ARB
• Concomitant aliskiren use in diabetic patients
• Pregnancy (discontinue immediately if detected)

Medication Adjustments

Continue These Therapies

• Beta-blockers (metoprolol succinate, carvedilol, bisoprolol) remain cornerstone therapy 3
• Mineralocorticoid receptor antagonists (spironolactone, eplerenone) should be continued 7, 6
• SGLT2 inhibitors (dapagliflozin, empagliflozin) provide additional benefit 6

Adjust These Medications

• Diuretics: May need dose reduction due to enhanced natriuresis with sacubitril/valsartan 6, 3
• Statins: Consider lower doses of OATP1B1/1B3 substrates (atorvastatin, rosuvastatin, simvastatin) due to potential drug interactions 6

Common Pitfalls to Avoid

• Don't delay initiation due to asymptomatic hypotension or mild laboratory changes 6
• Don't underdose due to excessive caution—benefits are dose-dependent 3
• Don't permanently discontinue for temporary side effects when dose reduction and re-titration is appropriate 6
• Don't skip the 36-hour ACE inhibitor washout period—this is mandatory to prevent angioedema 3, 4, 5
• Don't co-administer with ACE inhibitors or ARBs—this is contraindicated 4

Evidence Quality and Strength

The recommendation for in-hospital initiation is supported by:

• High-quality RCT evidence from PIONEER-HF (2019) demonstrating safety and efficacy 1
• Class IB guideline recommendation from European and American societies for HFrEF patients 8
• Consistent mortality benefit (20% reduction in cardiovascular death and HF hospitalization vs enalapril) established in PARADIGM-HF 5, 9
• FDA approval for chronic HFrEF to reduce cardiovascular death and hospitalization 4