What are the indications for Angiotensin Receptor-Neprilysin Inhibitors (ARNI)?

Indications for ARNI (Angiotensin Receptor-Neprilysin Inhibitor)

ARNI is indicated to reduce cardiovascular death and heart failure hospitalization in adult patients with chronic heart failure and reduced ejection fraction (HFrEF, LVEF ≤40%), particularly those with NYHA class II-III symptoms. 1, 2

Primary Indication: Heart Failure with Reduced Ejection Fraction (HFrEF)

Adult Patients

• ARNI is a Class I (strongest) recommendation for patients with HFrEF (LVEF <40%) and NYHA class II-III symptoms to reduce morbidity and mortality. 1
• ARNI reduced the composite endpoint of cardiovascular death or HF hospitalization by 20% compared to enalapril in the landmark PARADIGM-HF trial. 1
• For patients already tolerating an ACE inhibitor or ARB with chronic symptomatic HFrEF NYHA class II-III, replacement with ARNI is recommended to further reduce morbidity and mortality (Class I recommendation). 1

Acute Decompensated Heart Failure

• ARNI can be initiated as de novo treatment in hospitalized patients with acute HF before discharge after hemodynamic stabilization (systolic BP >100 mmHg, no vasopressor requirement). 3
• The PIONEER-HF trial demonstrated that ARNI initiated after hemodynamic stabilization reduced NT-proBNP levels without increased adverse events compared to enalapril. 3

Pediatric Patients

• ARNI is indicated for symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. 2
• The drug reduces NT-proBNP and is expected to improve cardiovascular outcomes in this population. 2

Secondary Indication: Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)

• For patients with HFmrEF (LVEF 41-49%), ARNI may be considered (Class 2b recommendation), particularly in those with LVEF on the lower end of this spectrum. 1
• This is a weaker recommendation compared to HFrEF, reflecting less robust evidence in this population. 1

Emerging Indication: Heart Failure with Preserved Ejection Fraction (HFpEF)

• ARNI has a Class 2b recommendation for HFpEF (LVEF ≥50%), indicating it may be considered but with less certainty of benefit. 1
• Current evidence does not show the same magnitude of benefit in HFpEF as seen in HFrEF. 4

Post-Myocardial Infarction with Left Ventricular Dysfunction

• ARNI may be used in patients with acute MI complicated by LVSD (LVEF ≤40%), heart failure, or both, as an alternative to ACE inhibitors. 1
• The ARNI contains valsartan (an ARB component), which fulfills guideline criteria for post-MI LVSD management. 1

Critical Eligibility Requirements

Patient Must Meet ALL of the Following:

• LVEF ≤40% (for strongest indication) 1, 3
• NYHA class II-III symptoms (or acute decompensation with stabilization) 1, 3
• Systolic blood pressure >100 mmHg 3
• No current vasopressor requirement 3
• eGFR >30 mL/min/1.73 m² (dose adjustment needed if <30) 2
• Serum potassium <5.0 mEq/L 1, 3

Absolute Contraindications (Do NOT Use)

• History of angioedema related to previous ACE inhibitor or ARB therapy (Class 3: Harm) 3, 2
• Concomitant use with ACE inhibitors or within 36 hours of last ACE inhibitor dose (Class 3: Harm) 3, 2
• Concomitant use with aliskiren in patients with diabetes 2
• Pregnancy (causes fetal toxicity and death) 2
• Hypersensitivity to any component 2

Position in Treatment Algorithm

ARNI is now considered a foundational medication in the "quadruple therapy" for HFrEF, alongside beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors. 1

• These four medication classes may be started simultaneously at initial low doses or sequentially without need to achieve target dosing before initiating the next medication. 1
• ARNI is preferred over ACE inhibitors or ARBs as first-line renin-angiotensin system inhibition in eligible HFrEF patients. 1
• ACE inhibitors or ARBs should only be used when ARNI is not feasible (e.g., cost, availability, patient preference). 1

Common Pitfall to Avoid

The most critical error is initiating ARNI while a patient is still taking an ACE inhibitor or within 36 hours of the last ACE inhibitor dose—this significantly increases angioedema risk. 3, 2 Always ensure a 36-hour washout period when switching from an ACE inhibitor to ARNI. 3