Why ACE Inhibitors Must Be Held When Starting ARNI
ACE inhibitors must be completely stopped with a mandatory 36-hour washout period before initiating ARNI therapy to prevent life-threatening angioedema caused by dangerous accumulation of bradykinin when both pathways that break it down are simultaneously blocked. 1
The Mechanism Behind This Critical Safety Requirement
Both ACE inhibitors and neprilysin inhibitors prevent the breakdown of bradykinin through different enzymatic pathways 1, 2:
- ACE inhibitors block angiotensin-converting enzyme, which normally degrades bradykinin
- Neprilysin inhibitors (the component of ARNI) block the neprilysin enzyme, which also normally degrades bradykinin
- Dual blockade of both pathways causes bradykinin to accumulate to dangerous levels, directly triggering angioedema 1, 2
This mechanism was tragically demonstrated with omapatrilat, a combined ACE inhibitor and neprilysin inhibitor that was terminated from development due to unacceptably high rates of angioedema—showing a 3-fold increased risk compared to enalapril alone, with Black patients and smokers at particularly high risk 1.
The Mandatory 36-Hour Washout Protocol
The ACC/AHA guidelines provide a Class III: Harm recommendation (meaning concomitant use causes harm and must be avoided) for administering ARNI within 36 hours of the last ACE inhibitor dose. 1
Specific Implementation Steps:
- Stop the ACE inhibitor completely and document the exact date and time of the last dose 2, 3
- Wait exactly 36 hours before administering the first dose of ARNI—this is mandatory and non-negotiable 1, 2, 3
- Consider longer washout periods in patients with a history of angioedema, though specific duration is not defined in guidelines 2
- No washout is required when switching from an ARB to ARNI, as ARBs do not block bradykinin breakdown through the same mechanism 2
Clinical Consequences of Non-Adherence
The evidence from clinical trials demonstrates the severity of this risk 1:
- Omapatrilat caused such significant morbidity from angioedema that its entire clinical development program was terminated 1
- Angioedema involving the tongue, glottis, or larynx can be fatal due to airway obstruction 3
- Because of these risks, patients with any history of angioedema were completely excluded from the PARADIGM-HF trial that established ARNI efficacy 1
Additional Safety Monitoring During Transition
Beyond the washout period, several monitoring steps are essential 2:
- Educate patients about early signs of angioedema: facial swelling, tongue swelling, difficulty breathing 2
- Monitor blood pressure within 1-2 weeks after the switch, as ARNI can cause hypotension 2, 3
- Reassess renal function and potassium within 1-2 weeks 2, 3
- Optimize volume status before initiating ARNI to minimize hypotension risk 2
Common Pitfalls to Avoid
Never use ACE inhibitors and ARNI concurrently—this is explicitly contraindicated and carries a Class III: Harm designation 1, 3. The FDA drug label for sacubitril/valsartan specifically states: "Do not take Sacubitril and Valsartan Tablets for at least 36 hours before or after you take an ACE inhibitor medicine" 3.
The 36-hour rule does not apply when simply switching from an ACE inhibitor to a standard ARB (without neprilysin inhibition), though monitoring for angioedema remains prudent given 2-17% cross-reactivity risk 2.
Absolute contraindications to ARNI include 1, 3:
- History of angioedema with ACE inhibitors or ARBs
- Current ACE inhibitor use or <36 hours since last dose
- Hereditary angioedema
Why This Matters for Patient Outcomes
Despite the washout requirement, the transition is worth the effort. ARNI demonstrated superior outcomes compared to enalapril in PARADIGM-HF, with a 20% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization 1, 4. However, these benefits can only be safely realized when the mandatory washout period is strictly observed to prevent the potentially fatal complication of angioedema 1, 2.