Contraindications to Entresto (Sacubitril/Valsartan)
Entresto is absolutely contraindicated in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy, with concomitant ACE inhibitor use (or within 36 hours of switching), in patients with hypersensitivity to any component, and with concomitant aliskiren use in diabetic patients. 1
Absolute Contraindications
The FDA label and guidelines identify four absolute contraindications where Entresto must not be used:
History of angioedema: Patients who experienced angioedema with previous ACE inhibitor or ARB therapy cannot receive Entresto due to significantly increased risk of recurrent, potentially fatal angioedema 2, 1. This is a Class 3 (Harm) recommendation 3.
Concomitant ACE inhibitor use: Do not administer Entresto within 36 hours of switching from or to an ACE inhibitor 2, 3, 1. This mandatory washout period reduces angioedema risk, as concomitant use dramatically increases this life-threatening complication 4, 2.
Hypersensitivity: Any known hypersensitivity to sacubitril, valsartan, or any component of the formulation is an absolute contraindication 1.
Aliskiren in diabetic patients: Concomitant use with aliskiren is contraindicated in patients with diabetes 1.
Relative Contraindications and High-Risk Situations
Several clinical scenarios require extreme caution or may preclude Entresto use:
Severe hypotension: Use with caution in patients with systolic blood pressure <100 mmHg 2, 1. Entresto lowers blood pressure and may cause symptomatic hypotension, particularly in volume-depleted patients or those on high-dose diuretics 1.
Severe renal impairment: Patients with eGFR <30 mL/min/1.73m² require dose adjustment (start at half the usual dose) rather than complete avoidance 2, 1. However, this represents a high-risk situation requiring close monitoring.
Severe hepatic impairment: Use is not recommended in patients with severe hepatic impairment (Child-Pugh C classification) 1. Moderate hepatic impairment (Child-Pugh B) requires starting at half the usual dose 1.
Hereditary angioedema: Entresto should not be used in patients with hereditary angioedema 1.
Pregnancy: Entresto can cause fetal harm when administered during the second and third trimesters, reducing fetal renal function and increasing fetal/neonatal morbidity and death 1. When pregnancy is detected, discontinue Entresto unless no appropriate alternative exists and the drug is considered lifesaving for the mother 1.
Critical Clinical Pearls
The 36-hour washout period when switching from an ACE inhibitor is mandatory and non-negotiable 2, 3, 1. This is the most common prescribing error and significantly increases angioedema risk. ARBs may be used as alternatives in patients with angioedema history 2.
Black patients have a higher rate of angioedema with Entresto compared to non-Black patients 1. Any patient with prior angioedema history (regardless of cause) is at increased risk 1.
Volume or salt depletion must be corrected prior to Entresto initiation, or therapy should start at a lower dose 1. Patients on high-dose diuretics are at particular risk for symptomatic hypotension 1.
If angioedema occurs, discontinue Entresto immediately and do not re-administer 1. Angioedema involving the tongue, glottis, or larynx requires immediate epinephrine administration (0.3-0.5 mL of 1:1000 solution subcutaneously) and airway management 1.
Monitoring Requirements
When Entresto is initiated despite relative contraindications: