What is the purpose of the 36-hour washout period when switching from an Angiotensin-Converting Enzyme (ACE) inhibitor to an Angiotensin Receptor Blocker (ARB), or vice versa?

The 36-Hour Washout Period: Prevention of Life-Threatening Angioedema

A mandatory 36-hour washout period must be strictly observed when switching from an ACE inhibitor to an ARNI (angiotensin receptor-neprilysin inhibitor) to prevent potentially fatal angioedema. 1

Why the 36-Hour Washout Exists

The washout period is required because both ACE inhibitors and neprilysin inhibitors block the breakdown of bradykinin through different pathways 1:

• ACE inhibitors prevent bradykinin degradation by blocking angiotensin-converting enzyme
• Neprilysin inhibitors (the component of ARNIs) also prevent bradykinin breakdown by blocking the neprilysin enzyme
• Dual blockade of both pathways simultaneously causes dangerous accumulation of bradykinin, which directly triggers angioedema 1

The historical precedent comes from omapatrilat, a combined ACE inhibitor-neprilysin inhibitor that was terminated in development due to unacceptable rates of angioedema and associated significant morbidity 1.

Critical Implementation Details

When switching FROM ACE inhibitor TO ARNI:

• Stop the ACE inhibitor completely
• Wait exactly 36 hours before administering the first dose of ARNI 1
• This washout is mandatory and non-negotiable - it carries a Class III: Harm recommendation 1
• Consider longer washout periods in patients with history of angioedema, though specific duration is not defined 2

When switching FROM ARB TO ARNI:

• No washout period is required - you can switch immediately 1
• ARBs do not block bradykinin breakdown through the same mechanism as ACE inhibitors

Common Clinical Scenarios

For hospitalized patients with heart failure:

• The 36-hour washout must be observed even in the inpatient setting where rapid optimization is desired 3, 4
• Real-world data shows only 67% adherence to the full washout period in practice, though no angioedema events occurred in one small study 4
• Despite the temptation to expedite therapy, strict adherence is essential given the potentially life-threatening consequences

Monitoring during the transition:

• Patients should be educated about early signs of angioedema (facial swelling, tongue swelling, difficulty breathing) 5
• Blood pressure should be monitored within 1-2 weeks after the switch 1
• Renal function and potassium should be reassessed within 1-2 weeks 1

Important Caveats

This washout applies specifically to ARNI therapy:

• The 36-hour rule is not required when simply switching from an ACE inhibitor to a standard ARB (without neprilysin inhibition) 2
• When switching ACE inhibitor to ARB alone, you can transition immediately, though monitoring for angioedema remains prudent given 2-17% cross-reactivity risk 5

Never combine these medications:

• ARNI should never be administered concomitantly with ACE inhibitors 1
• Dual blockade of the renin-angiotensin system with ACE inhibitor + ARB is potentially harmful and should be avoided 1, 6

Patient-specific considerations:

• Patients with prior angioedema on ACE inhibitors require extreme caution even with the washout period 5
• Volume status should be optimized before initiating ARNI to minimize hypotension risk 1
• Potassium must be <5.2 mmol/L before ARNI initiation 3