Sacubitril/valsartan (ARNI) is approved for heart failure with reduced ejection fraction (HFrEF). What is the critical washout period required between ACE inhibitor discontinuation and starting sacubitril/valsartan, and why?

• A 24 hours; to prevent first-dose hypotension
• B 36 hours (≥5 half-lives); to prevent angioedema from dual neprilysin and ACE inhibition potentiating bradykinin accumulation ✓
• C 36 hours; to allow complete renal clearance of the ACE inhibitor
• D 7 days; to allow cardiac remodeling reversal from the ACE inhibitor

Explanation

Sacubitril inhibits neprilysin (neutral endopeptidase), which degrades bradykinin. ACE inhibitors also prevent bradykinin degradation (by blocking kininase II/ACE). Concurrent use doubles bradykinin accumulation, causing life-threatening angioedema — particularly affecting the airway. A mandatory washout of ≥36 hours (equivalent to 5 half-lives of most ACEIs) between ACEI discontinuation and ARNI initiation is required per guidelines. This is one of the most tested clinical precautions for this drug class.

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

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