Transitioning from ACE Inhibitor to Entresto (Sacubitril/Valsartan)
You must ensure a mandatory 36-hour washout period between stopping the ACE inhibitor and starting sacubitril/valsartan to minimize the risk of angioedema. 1, 2
Critical Pre-Switch Requirements
Before initiating the transition, verify the following:
- Washout period: Stop the ACE inhibitor and wait a full 36 hours before administering the first dose of sacubitril/valsartan 1, 2
- No history of angioedema: Sacubitril/valsartan is contraindicated in patients with prior angioedema related to ACE inhibitor or ARB use 1, 2
- Hemodynamic stability: Ensure systolic blood pressure ≥100 mm Hg (patients with borderline BP require careful monitoring) 1
- Renal function: Verify eGFR >30 mL/min/1.73 m² 1
- Electrolytes: Confirm potassium <5.2 mmol/L 3
- Volume status: Ensure patient is not volume-depleted, as this increases hypotension risk 1
Initial Dosing Strategy
The starting dose depends on the patient's previous ACE inhibitor dose equivalency: 1
- If on low-dose ACE inhibitor (equivalent to <10 mg enalapril daily): Start sacubitril/valsartan 24/26 mg twice daily 1, 4
- If on high-dose ACE inhibitor (equivalent to ≥10 mg enalapril daily): Start sacubitril/valsartan 49/51 mg twice daily 1, 4
Special populations requiring lower starting dose (24/26 mg twice daily): 1, 4
- Severe renal impairment (eGFR <30 mL/min/1.73 m²)
- Moderate hepatic impairment (Child-Pugh Class B)
- Systolic blood pressure <100 mm Hg
- Age ≥75 years
Titration Protocol
Double the dose every 2-4 weeks as tolerated, targeting the maintenance dose of 97/103 mg twice daily. 1, 4, 2
- Assess tolerability at each step before advancing 1
- Monitor blood pressure, electrolytes (especially potassium), and renal function after each dose increase 1, 4
- Check labs within 1-2 weeks after initiation or dose adjustment 4
- Continue uptitration even if symptoms improve at lower doses, as clinical trial benefits were demonstrated at target doses 5
Managing Common Adverse Effects
Hypotension: 1
- If symptomatic hypotension occurs without congestion, consider empirically reducing loop diuretic dose
- Reassess need for other vasodilators (nitrates, calcium channel blockers)
- In borderline blood pressure patients, careful administration and close follow-up are essential
Hyperkalemia or worsening renal function: 4
- Monitor potassium and creatinine closely
- If potassium rises to 5.5-6.0 mmol/L, reduce aldosterone antagonist dose if on concurrent therapy
- If potassium >6.0 mmol/L, stop aldosterone antagonist and treat hyperkalemia
Angioedema risk: 6
- The 36-hour washout minimizes overlapping ACE and neprilysin inhibition 6
- Confirmed angioedema occurred in only 0.45% of patients on sacubitril/valsartan versus 0.24% on enalapril in PARADIGM-HF 6
- Risk is higher in Black patients 6
- Most events are mild; only 5 patients in PARADIGM-HF required hospitalization and none required mechanical airway support 6
Clinical Context and Evidence
The 2021 ACC Expert Consensus Decision Pathway now supports direct-to-ARNI initiation without prior ACE inhibitor exposure in appropriate patients, based on PIONEER-HF and PROVE-HF data showing safety and efficacy 1. However, when switching from an existing ACE inhibitor, the 36-hour washout remains mandatory due to the distinct mechanism of angioedema risk when combining ACE inhibition with neprilysin inhibition 2, 6.
Sacubitril/valsartan is preferred over ACE inhibitors/ARBs in NYHA class II-III HFrEF patients, as PARADIGM-HF demonstrated a 20% relative reduction in cardiovascular death or heart failure hospitalization compared to enalapril 4, 7. This represents a Class 1, Level B-R recommendation in current guidelines 4.
The transition can be performed in both outpatient and inpatient settings, though inpatient initiation after acute decompensation is feasible once hemodynamic stability is achieved 1, 3. Up to 25% of patients may develop hypotension during initiation, so ensuring adequate volume status is critical 1.