What are the contraindications for Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)?

Contraindications for ARNI (Angiotensin Receptor-Neprilysin Inhibitors)

ARNIs are absolutely contraindicated in patients with a history of angioedema (from any cause), those currently taking or who have taken an ACE inhibitor within the past 36 hours, patients with hypersensitivity to any component, and those with diabetes taking aliskiren. 1

Absolute Contraindications

History of Angioedema

• Any prior angioedema episode—whether related to ACE inhibitors, ARBs, or idiopathic—is an absolute contraindication to ARNI therapy. 2, 1
• The mechanism involves dual inhibition of both ACE and neprilysin, which both break down bradykinin, leading to dangerous bradykinin accumulation and potentially life-threatening angioedema. 2, 3
• Historical data from omapatrilat (a combined ACE inhibitor/neprilysin inhibitor) showed a 3-fold increased risk of angioedema compared to enalapril, with particularly high risk in Black patients and smokers, ultimately leading to termination of its development. 2, 3
• Hereditary angioedema is also a contraindication. 1

Concomitant ACE Inhibitor Use

• ARNIs must not be administered with ACE inhibitors or within 36 hours of the last ACE inhibitor dose. 2, 1
• This is a Class III (Harm) recommendation from the ACC/AHA/HFSA guidelines. 2
• The 36-hour washout period is mandatory to allow adequate clearance and prevent the catastrophic angioedema risk from dual bradykinin pathway inhibition. 3

Hypersensitivity

• Known hypersensitivity to sacubitril, valsartan, or any component of the formulation is an absolute contraindication. 1

Aliskiren in Diabetic Patients

• Concomitant use with aliskiren in patients with diabetes mellitus is contraindicated. 1

Critical Safety Warnings and High-Risk Populations

Angioedema Risk Stratification

• Black patients have a significantly higher rate of angioedema with ARNIs compared to non-Black patients. 2, 1
• Smokers are at particularly elevated risk based on neprilysin inhibitor data. 2, 3
• The angioedema risk is highest during the transition period from ACE inhibitors and during early treatment phases. 3

Pregnancy

• ARNIs cause fetal toxicity and are contraindicated in pregnancy, particularly during the second and third trimesters. 1
• Drugs acting on the renin-angiotensin system reduce fetal renal function and increase fetal/neonatal morbidity and mortality. 1
• When pregnancy is detected, discontinue ARNI immediately and consider alternative therapy. 1

Relative Contraindications and Cautions

Severe Hypotension

• Patients with systolic blood pressure <100 mm Hg require careful assessment before initiation. 3
• Volume or salt depletion should be corrected prior to ARNI administration. 1

Severe Renal Impairment

• While not contraindicated, patients with eGFR <30 mL/min/1.73 m² require dose adjustment (start at half the usual dose). 1

Severe Hepatic Impairment

• Use is not recommended in patients with severe hepatic impairment (Child-Pugh C). 1
• Moderate hepatic impairment (Child-Pugh B) requires starting at half the usual dose. 1

Common Pitfalls to Avoid

• Never assume a patient without documented angioedema history is safe—actively screen for any prior episodes of unexplained facial, lip, tongue, or throat swelling. 2
• Do not shorten the 36-hour ACE inhibitor washout period even if the patient appears stable, as this dramatically increases angioedema risk. 3
• Educate all patients about angioedema symptoms (lip/tongue/throat swelling, difficulty breathing) and instruct them to seek emergency care immediately if these occur. 3
• Cross-reactivity exists—patients who developed angioedema with ARBs should also be considered at increased risk and ARNI use should be avoided. 2, 4