What treatment is recommended for ARNI (Angiotensin-Receptor Neprilysin Inhibitor)?

ARNI Treatment for Heart Failure with Reduced Ejection Fraction

ARNI (sacubitril/valsartan) is recommended as the preferred renin-angiotensin system inhibitor for patients with chronic symptomatic HFrEF (NYHA class II-III) who can tolerate an ACE inhibitor or ARB, as it significantly reduces cardiovascular death and heart failure hospitalization compared to ACE inhibitors alone. 1

Primary Indication and Patient Selection

ARNI should replace ACE inhibitors or ARBs in patients with:

• Chronic symptomatic HFrEF with NYHA class II or III symptoms 1
• Left ventricular ejection fraction ≤40% 1
• Elevated natriuretic peptides (BNP >150 pg/mL or NT-proBNP ≥600 pg/mL; OR BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL with hospitalization in preceding 12 months) 1
• Ability to tolerate target doses of enalapril 10 mg twice daily or equivalent ACE inhibitor/ARB 1

Clinical Evidence and Outcomes

The PARADIGM-HF trial demonstrated that sacubitril/valsartan reduced the composite endpoint of cardiovascular death or HF hospitalization by 20% compared to enalapril, with benefits seen equally for both death and hospitalization 1. This mortality and morbidity benefit establishes ARNI as superior to traditional ACE inhibitor therapy 1.

Initiation Strategies

ARNI can be initiated through two approaches:

De Novo Initiation (Preferred in Hospitalized Patients)

• Start ARNI before discharge in patients hospitalized with acute decompensated HF 1
• The PIONEER-HF trial showed ARNI reduced NT-proBNP levels without increased adverse events compared to enalapril 1
• This approach simplifies management by avoiding the need to uptitrate ACE inhibitors first and then switch 1

Transition from ACE Inhibitor or ARB

• Mandatory 36-hour washout period between last ACE inhibitor dose and first ARNI dose 1
• This washout prevents concurrent neprilysin and ACE inhibition, which increases angioedema risk 1
• ARBs do not require a washout period when switching to ARNI 1

Dosing and Titration

Target dose: sacubitril/valsartan 97/103 mg (equivalent to valsartan 160 mg) twice daily 1

Titration schedule:

• Start at low dose and increase every 2 weeks in stable patients 1
• Monitor blood pressure, renal function, and potassium at each titration 1
• May require reduction in loop diuretic doses to permit titration due to vasodilatory effects 1
• Longer titration intervals may be needed for frail patients or those with marginal hemodynamics 1

Absolute Contraindications

Do NOT administer ARNI in patients with:

• Any history of angioedema (Class III: Harm recommendation) 1
• Concomitant ACE inhibitor use or within 36 hours of last ACE inhibitor dose (Class III: Harm) 1
• Pregnancy or plans to become pregnant 1

Monitoring and Adverse Effects

Common adverse effects requiring monitoring:

• Hypotension: More frequent with ARNI than enalapril; monitor blood pressure closely 1
• Renal insufficiency: Monitor creatinine and eGFR 1
• Hyperkalemia: Monitor potassium levels, may need to restrict dietary/supplemental potassium 1
• Angioedema: Comparable incidence to enalapril but still requires vigilance 1

Integration with Guideline-Directed Medical Therapy

ARNI should be used in conjunction with:

• Evidence-based beta-blockers 1
• Aldosterone antagonists in selected patients 1
• SGLT2 inhibitors (dapagliflozin or empagliflozin) 1

The benefit of ARNI is consistent even in patients already receiving these other guideline-directed therapies 1.

Alternative Options When ARNI Not Feasible

If ARNI cannot be used due to cost, contraindications, or intolerance:

• ACE inhibitors remain a high-value alternative (Class I recommendation) 1
• ARBs are recommended for patients intolerant to ACE inhibitors due to cough or angioedema 1
• These alternatives provide established mortality benefit, though inferior to ARNI 1

Economic Considerations

ARNI provides high economic value compared to ACE inhibitors despite higher upfront costs, due to reduced hospitalizations and mortality 1. However, out-of-pocket costs may approach $1,000 annually with Medicare coverage, which can be a barrier to adherence 1. Generic formulations will not be available until 2024 at earliest 1.