Sacubitril is a neprilysin inhibitor. When combined with valsartan in the ARNI sacubitril/valsartan (LCZ696), a crucial risk that was the main reason it cannot be combined with ACE inhibitors is:

• A Both drugs cause hyperkalaemia, and the combination results in fatal levels of potassium
• B ACE inhibitors and neprilysin both degrade bradykinin; their combined inhibition causes massive bradykinin accumulation and life-threatening angioedema ✓
• C Valsartan and ACE inhibitors both block the renin-angiotensin system at different levels, causing additive hypotension that causes renal failure
• D Neprilysin inhibition raises natriuretic peptide levels which competitively displace ACE inhibitors from ACE, causing drug failure

Explanation

ACE inhibitors block bradykinin degradation by ACE. Neprilysin (also called neutral endopeptidase) is another major enzyme degrading bradykinin. When both are inhibited simultaneously, bradykinin accumulates markedly, causing severe and potentially fatal angioedema. Therefore, sacubitril/valsartan is absolutely contraindicated with ACE inhibitors; a 36-hour washout period after stopping an ACE inhibitor is mandatory before starting sacubitril/valsartan. This combination was tested in the PARADIGM-HF trial, and this safety concern is a frequently tested NEET PG point.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.