What is the best course of action for a 43-year-old male with a history of heart failure, on Lasix (Furosemide) 40 mg orally twice a day, Carvedilol 6.25 mg orally twice a day, and Entresto (Sacubitril/Valsartan) 24-26 mg orally twice a day, presenting with nocturnal tongue swelling that improves with Lasix, but without evidence of fluid overload on examination?

Immediately Discontinue Entresto Due to Angioedema

This patient is experiencing angioedema from Entresto (sacubitril/valsartan), a potentially life-threatening adverse reaction that requires immediate and permanent discontinuation of the medication. The nocturnal tongue swelling that improves with diuresis is classic for angiotensin receptor-neprilysin inhibitor (ARNI)-induced angioedema, which can progress to airway obstruction and death 1, 2.

Why This is Angioedema, Not Fluid Overload

• The clinical presentation is pathognomonic for drug-induced angioedema: isolated tongue swelling occurring at night (when supine positioning may worsen it) without other signs of volume overload on examination 2
• The apparent "improvement" with Lasix is misleading: this likely represents coincidental timing or placebo effect, as angioedema is a non-pitting edema caused by bradykinin accumulation, not fluid retention that would respond to diuretics 2
• True volume overload would present with: elevated jugular venous pressure, peripheral edema, pulmonary congestion, weight gain, and orthopnea—none of which are described in this patient 3, 4

Immediate Management Steps

1. Stop Entresto Permanently

• Discontinue sacubitril/valsartan immediately and never rechallenge 1, 2
• The FDA label explicitly warns that angioedema can occur at any time during treatment and requires permanent discontinuation 1
• Patients who develop angioedema on ARNIs have a significantly elevated risk of recurrence and progression to life-threatening airway compromise 1, 2

2. Monitor for Airway Compromise

• Assess for tongue and floor-of-mouth edema progression, which are the primary indications for emergent intubation 2
• If massive tongue swelling develops with oropharyngeal involvement, proceed immediately to fiberoptic intubation before complete airway obstruction occurs 2
• Most angioedema cases resolve within 24-48 hours after drug discontinuation, though severe tongue edema may take up to 72 hours 2

3. Acute Angioedema Treatment Protocol

• Administer high-humidity face tent, intravenous antihistamines (initial bolus), and intravenous corticosteroids (continued course) 2
• Epinephrine may be considered for severe cases with respiratory distress 5
• Once medical treatment begins, angioedema typically does not progress further 2

Transition to Alternative Heart Failure Therapy

Switch to ACE Inhibitor with Extreme Caution

• Wait at least 36 hours after stopping Entresto before initiating an ACE inhibitor to allow neprilysin inhibition to wash out 1
• However, this patient has demonstrated angioedema susceptibility, which significantly increases the risk of ACE inhibitor-induced angioedema (up to 10-fold higher risk in patients with prior angioedema) 2
• If an ACE inhibitor is attempted, use the lowest starting dose and monitor intensively for 48-72 hours, as angioedema can occur within hours to years after initiation 5, 2

Consider Hydralazine-Nitrate Combination Instead

• For patients who cannot tolerate ACE inhibitors or ARBs due to angioedema, hydralazine-isosorbide dinitrate is the preferred alternative for neurohormonal blockade in heart failure with reduced ejection fraction 3
• This combination provides mortality benefit without the angioedema risk associated with renin-angiotensin system inhibitors 3

Maintain Beta-Blocker Therapy

• Continue carvedilol 6.25 mg twice daily without interruption, as beta-blockers reduce mortality and should not be discontinued even during clinical changes 3
• The current dose is suboptimal (target is 25 mg twice daily for carvedilol), so uptitrate gradually once the patient is stable 3

Optimize Diuretic Regimen

• Continue Lasix 40 mg twice daily as the patient has a history of heart failure requiring diuretics 6, 4
• The absence of current fluid overload does not warrant diuretic discontinuation, as maintenance diuretics prevent recurrent volume overload in patients with prior fluid retention 6
• Monitor daily weights and adjust diuretic dose to maintain euvolemia (target 0.5-1.0 kg daily weight loss if fluid retention recurs) 4

Critical Pitfalls to Avoid

• Do not rechallenge with Entresto or any ARNI: the risk of recurrent and potentially fatal angioedema is unacceptably high 1, 2
• Do not assume the tongue swelling is from fluid overload: angioedema is non-pitting and does not respond to diuretics, despite the temporal association this patient experienced 2
• Do not rush to start an ACE inhibitor: the 36-hour washout period is mandatory, and this patient's angioedema history makes ACE inhibitors high-risk 1, 2
• Do not discontinue beta-blocker therapy: abrupt withdrawal can cause clinical deterioration and increased mortality 3

Special Consideration for This Patient Population

• African-American patients have a 2-3 times higher risk of ARNI-induced angioedema compared to other populations 1
• If this patient is African-American, hydralazine-nitrate may be particularly appropriate as it has demonstrated superior outcomes in this population 3