When to use Angiotensin Receptor-Neprilysin Inhibitors (ARNI) in patients with heart failure with reduced ejection fraction (HFrEF), and how to monitor and adjust treatment?

ARNI in Heart Failure with Reduced Ejection Fraction: Indications, Monitoring, and Adjustment

When to Use ARNI

ARNI (sacubitril/valsartan) is recommended as first-line therapy for all patients with symptomatic HFrEF (NYHA class II-III) to reduce cardiovascular death and heart failure hospitalization, replacing ACE inhibitors or ARBs. 1

Primary Indications

• Chronic HFrEF patients with NYHA class II or III symptoms who are currently tolerating an ACE inhibitor or ARB should be switched to ARNI to further reduce morbidity and mortality 1
• De novo treatment in newly diagnosed HFrEF can be initiated with ARNI as first-line therapy to simplify management, though this has less robust data than switching strategies 1, 2
• Hospitalized patients with acute decompensated HF should receive ARNI before discharge after hemodynamic stabilization (systolic BP >100 mmHg, no vasopressor requirement), as this reduces NT-proBNP and improves health status 1, 3

Eligibility Criteria from PARADIGM-HF Trial

Patients must meet the following criteria 1:

• Mildly elevated natriuretic peptides: BNP >150 pg/mL or NT-proBNP ≥600 pg/mL, OR
• Lower natriuretic peptides with recent hospitalization: BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL with HF hospitalization in preceding 12 months
• Ability to tolerate target doses: Must tolerate enalapril 10 mg twice daily equivalent before switching

Integration with Guideline-Directed Medical Therapy

ARNI should be initiated as part of a four-pillar foundational therapy approach that includes 2:

• Beta-blocker
• Mineralocorticoid receptor antagonist (MRA)
• SGLT2 inhibitor (dapagliflozin or empagliflozin) 1

This combination provides high economic value and maximizes mortality reduction 1.

Absolute Contraindications

Do not use ARNI in the following situations 1, 4:

• History of angioedema (any prior episode, including ACE inhibitor or ARB-related) - Class III: Harm recommendation 1
• Concomitant ACE inhibitor use or within 36 hours of last ACE inhibitor dose - Class III: Harm recommendation 1
• Concomitant use with aliskiren in patients with diabetes 4
• Hypersensitivity to any component 4

Dosing and Titration Strategy

Starting Doses

Standard starting dose: 49/51 mg (sacubitril/valsartan) orally twice daily 4

Reduced starting dose (24/26 mg twice daily) for 4:

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Moderate hepatic impairment
• Patients previously on low-dose ACE inhibitor/ARB
• Systolic blood pressure 100-110 mmHg

Titration Protocol

• Target maintenance dose: 97/103 mg twice daily 1, 4
• Titration interval: Every 2-4 weeks as tolerated 1, 3
• Dose escalation sequence: 24/26 mg → 49/51 mg → 97/103 mg twice daily 4

Switching from ACE Inhibitor/ARB

Mandatory 36-hour washout period between last ACE inhibitor dose and first ARNI dose to minimize angioedema risk 1

ARBs can be switched immediately without washout, but ACE inhibitors require the full 36-hour interval 1.

Monitoring Parameters

Initial Monitoring (Within 1-2 Weeks of Initiation or Dose Increase)

Monitor the following parameters 2, 4:

• Blood pressure: Watch for symptomatic hypotension, particularly in volume-depleted patients or those with systolic BP <100 mmHg 1, 2
• Serum creatinine/eGFR: Check for worsening renal function (>30% increase warrants dose adjustment or discontinuation) 2, 5
• Serum potassium: Monitor for hyperkalemia (>5.0 mEq/L requires caution; >5.5 mEq/L may require dose reduction) 1, 2, 3

Ongoing Monitoring

• Natriuretic peptide levels: Prefer NT-proBNP over BNP for clinical follow-up, especially during first 8-10 weeks, as sacubitril inhibits neprilysin which degrades BNP, causing falsely elevated BNP levels 6
• Longitudinal increases in either BNP or NT-proBNP after the initial period remain prognostic markers of adverse events 6
• Clinical symptoms: Assess NYHA class and functional status at each visit 5, 7

Signs of Angioedema (Rare but Serious)

Monitor for 1:

• Facial, lip, or tongue swelling
• Difficulty breathing or swallowing
• Discontinue immediately if angioedema occurs

Dose Adjustment Strategies

For Hypotension

If symptomatic hypotension occurs 1, 2:

• Optimize volume status first (reduce diuretic dose if appropriate)
• Adjust timing of other BP-lowering medications
• Consider temporary dose reduction of ARNI
• Reassess and uptitrate when blood pressure stabilizes

For Renal Dysfunction

If eGFR decreases >30% from baseline 5:

• Hold ARNI temporarily
• Assess for reversible causes (volume depletion, NSAIDs, contrast exposure)
• Restart at lower dose once eGFR stabilizes
• ARNI can be used cautiously even in advanced CKD (stages 4-5) with close monitoring 5

For Hyperkalemia

If potassium >5.5 mEq/L 1, 3:

• Review concomitant medications (MRA, potassium supplements, NSAIDs)
• Consider dietary potassium restriction
• May require dose reduction or temporary discontinuation
• Use potassium binders if needed to maintain ARNI therapy

Common Pitfalls and How to Avoid Them

Pitfall 1: Inadequate Washout from ACE Inhibitor

Solution: Ensure full 36-hour washout period to minimize angioedema risk 1

Pitfall 2: Using BNP Instead of NT-proBNP for Monitoring

Solution: Prefer NT-proBNP for clinical follow-up as BNP levels rise artificially due to neprilysin inhibition 6

Pitfall 3: Discontinuing ARNI for Mild Hypotension

Solution: Optimize volume status and timing of other medications before reducing ARNI dose, as mild hypotension is expected and not harmful if asymptomatic 1, 2

Pitfall 4: Avoiding ARNI in Advanced CKD

Solution: ARNI can be used safely in CKD stages 4-5 with careful monitoring of eGFR and potassium 5

Pitfall 5: Undertitration to Target Dose

Solution: Systematically uptitrate every 2-4 weeks to reach target dose of 97/103 mg twice daily, as only 41.6% of real-world patients achieve adequate dosing 7

Clinical Outcomes

The PARADIGM-HF trial demonstrated that ARNI reduced 1, 8:

• Composite endpoint of cardiovascular death or HF hospitalization by 20%
• Cardiovascular death by 20%
• Heart failure hospitalization by 21%
• All-cause mortality by 16%

These benefits were consistent across all prespecified subgroups and provide high economic value compared to ACE inhibitors 1.