What are the guidelines for using Angiotensin Receptor-Neprilysin Inhibitor (ARNI) in patients with heart failure?

Guidelines for Using Angiotensin Receptor-Neprilysin Inhibitor (ARNI) in Heart Failure

ARNi therapy (sacubitril/valsartan) is recommended as first-line therapy for patients with heart failure with reduced ejection fraction (HFrEF) with NYHA class II-III symptoms to reduce morbidity and mortality. 1

Patient Selection for ARNi Therapy

Primary Indications

• HFrEF patients (LVEF ≤40%) 1
  • Recommended for patients with current or prior symptoms
  • Can be used as initial therapy or as replacement for ACEi/ARB
  • Particularly beneficial in patients who remain symptomatic despite optimal medical therapy

Specific Populations

• Hospitalized HFrEF patients: ARNi can be initiated before discharge in the absence of contraindications 1
• Chronic symptomatic HFrEF patients: Should be switched from ACEi/ARB to ARNi if they tolerate the former 1
• De novo treatment: Can be initiated in treatment-naïve patients to simplify management 1

Contraindications

• History of angioedema: ARNi should never be administered to patients with any history of angioedema 1, 2
• Concomitant ACEi use: ARNi must not be administered with ACEi due to increased risk of angioedema 1, 2
• Pregnancy: ARNi should not be given to pregnant patients or those planning pregnancy 1
• Severe hepatic impairment (Child-Pugh C): Not recommended 3

Dosing and Administration

Initiation Protocol

1. When switching from ACEi to ARNi:

   • Mandatory 36-hour washout period after last ACEi dose 1, 2
   • This prevents excessive bradykinin accumulation and risk of angioedema

2. When switching from ARB to ARNi:

   • No washout period required 2
   • Can be started immediately after the last ARB dose

3. Starting doses:

   • Standard: 49/51 mg twice daily for most patients 2, 3
   • Reduced: 24/26 mg twice daily for:
     • Severe renal impairment (eGFR <30 mL/min/1.73m²) 3
     • Moderate hepatic impairment (Child-Pugh B) 3
     • Elderly patients who may be at risk for hypotension

4. Titration:

   • Increase dose every 2-4 weeks as tolerated 2
   • Target dose: 97/103 mg twice daily 2, 3

Monitoring and Safety

Initial Monitoring

• Blood pressure (risk of hypotension)
• Renal function (risk of worsening renal function)
• Serum potassium (risk of hyperkalemia)
• Signs of angioedema

Ongoing Monitoring

• Regular assessment of blood pressure, renal function, and electrolytes
• Symptoms of heart failure
• Medication adherence and tolerability

Common Adverse Effects

• Hypotension (more common than with ACEi) 1
• Renal insufficiency
• Hyperkalemia
• Angioedema (comparable incidence to ACEi) 1

Clinical Benefits

Established Benefits in HFrEF

• 20% reduction in composite endpoint of cardiovascular death or HF hospitalization compared to ACEi 1, 4
• Benefits observed consistently across the LVEF spectrum within HFrEF range 5
• Reduction in both cardiovascular mortality and HF hospitalizations 1, 4

Special Considerations

• Benefits are consistent across subgroups including age, sex, etiology of HF, and comorbidities 6
• ARNi therapy has been successfully implemented in pharmacist-managed clinics with high rates of achieving target doses 7
• Loop and thiazide diuretic requirements may decrease after ARNi initiation 7

Common Pitfalls and Caveats

1. Failure to observe ACEi washout period: Must wait 36 hours after last ACEi dose before starting ARNi to prevent angioedema 1, 2

2. Inadequate blood pressure monitoring: ARNi is associated with higher rates of symptomatic hypotension compared to ACEi 1

3. Inappropriate use in angioedema history: Patients with any history of angioedema should never receive ARNi 1, 2

4. Suboptimal dosing: Many patients can achieve target doses (97/103 mg twice daily) with appropriate titration 7

5. Delayed initiation: Guidelines support early initiation of ARNi in eligible patients rather than waiting for clinical deterioration on ACEi/ARB therapy 1

By following these evidence-based guidelines for ARNi use in heart failure, clinicians can optimize outcomes for patients with HFrEF while minimizing potential adverse effects.