A 68-year-old man with HFrEF is on lisinopril, carvedilol, and furosemide. His physician adds sacubitril/valsartan (Entresto) but first discontinues lisinopril. The mandatory 36-hour washout period before starting sacubitril/valsartan is required to prevent:
- A Additive first-dose hypotension from dual renin-angiotensin blockade
- B Hyperkalaemia from simultaneous ACE inhibition and angiotensin receptor blockade
- C Life-threatening angioedema due to combined inhibition of both ACE and neprilysin, causing excessive bradykinin accumulation ✓
- D Serotonin syndrome from interaction between lisinopril's sulphydryl group and neprilysin substrates
Correct answer: C. Life-threatening angioedema due to combined inhibition of both ACE and neprilysin, causing excessive bradykinin accumulation
Explanation
Sacubitril inhibits neprilysin (neutral endopeptidase), which normally degrades bradykinin. ACE inhibitors also prevent bradykinin degradation. Using both together causes dramatic accumulation of bradykinin, significantly increasing the risk of angioedema, which can be life-threatening if involving the larynx. A 36-hour washout (or 48 hours if clinically feasible) is mandatory. Hyperkalaemia and hypotension are concerns with RAAS combinations but do not drive the mandatory washout period.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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