How should a patient be switched from an ACE inhibitor or ARB to an angiotensin‑receptor‑neprilysin inhibitor (ARNI) and what are the risks of an improper switch?

How to Switch from ACE Inhibitor/ARB to ARNI

When switching from an ACE inhibitor to an ARNI, you must wait at least 36 hours between the last ACE inhibitor dose and the first ARNI dose to prevent life-threatening angioedema. 11

The Critical Washout Period

The 36-hour washout period is mandatory when transitioning from an ACE inhibitor to ARNI, but not required when switching from an ARB to ARNI 11. This distinction is crucial:

• From ACE inhibitor: Stop the ACE inhibitor and wait a full 36 hours before starting ARNI
• From ARB: Can switch directly without a washout period

Step-by-Step Switching Protocol

Starting Doses

Begin ARNI at 24/26 mg twice daily (or 49/51 mg twice daily if the patient was on moderate-to-high doses of ACE inhibitor/ARB and has good blood pressure tolerance) 1

Titration Schedule

• Increase the dose every 2-4 weeks as tolerated
• Target dose: 97/103 mg twice daily
• Monitor blood pressure, renal function, and potassium at each titration step

Monitoring Parameters

Check the following before each dose increase:

• Blood pressure: Watch for symptomatic hypotension (most common adverse effect)
• Serum creatinine/eGFR: Monitor for worsening renal function
• Serum potassium: Keep <5.0 mEq/L
• Symptoms: Assess for dizziness, lightheadedness, or signs of hypoperfusion

Dangers of Improper Switching

Angioedema Risk (Most Serious)

Concurrent use or insufficient washout between ACE inhibitor and ARNI dramatically increases angioedema risk 11. Both medications affect bradykinin metabolism—ACE inhibitors prevent bradykinin breakdown, while neprilysin inhibition (in ARNI) also increases bradykinin levels. The combined effect can cause:

• Life-threatening airway swelling
• Tongue and facial edema
• Respiratory compromise requiring emergency intervention

Absolute contraindications:

• Any history of angioedema (from any cause) 1
• Concurrent ACE inhibitor use 1
• Less than 36 hours since last ACE inhibitor dose 11

Other Risks of Improper Switching

Symptomatic hypotension occurs more frequently with ARNI than ACE inhibitors 11. Starting too quickly or at too high a dose, especially without the washout period, compounds this risk.

Clinical deterioration can occur if you abruptly stop ACE inhibitor therapy without bridging to ARNI, particularly if the patient doesn't tolerate ARNI and you have no backup plan 1.

Real-World Adherence Data

A 2024 study found that only 67% of patients received the full 36-hour washout in actual practice 2. However, this study showed no angioedema events even in those with shorter washouts—but this does not justify skipping the washout, as the sample size was too small (n=33) to detect rare but serious events like angioedema.

Practical Clinical Pearls

• ARB switching is simpler: If the patient is on an ARB, you can switch directly to ARNI without waiting, making this the easier transition
• Inpatient initiation: The PIONEER-HF and TRANSITION trials support starting ARNI in hospitalized patients before discharge without increased adverse events 11
• De novo initiation: Consider starting ARNI directly in treatment-naïve patients to avoid the switching complexity altogether 11
• Pharmacist involvement: Pharmacist-led ARNI titration programs achieve target doses in 60.9% of patients versus only 18.0% with usual care 3

Common Pitfalls to Avoid

1. Starting ARNI too soon after ACE inhibitor: Always count the full 36 hours
2. Forgetting the washout doesn't apply to ARBs: This unnecessarily delays optimal therapy
3. Starting at too high a dose: Begin low, especially in patients with borderline blood pressure
4. Inadequate monitoring during titration: Check labs and blood pressure before each increase
5. Giving up on titration too early: Even intermediate doses provide benefit if target dose isn't tolerated 1