What is the best course of action for an obese patient with heart failure, on Entresto (sacubitril/valsartan), Carvedilol, and Lasix (furosemide), who presents with tongue swelling after 2 years on Entresto?

Immediately Discontinue Entresto Due to Angioedema

Your patient is experiencing angioedema from Entresto, which can be life-threatening and requires immediate discontinuation of the medication, even after 2 years of use. Angioedema associated with neprilysin inhibitors like sacubitril (component of Entresto) can occur at any time during treatment, from hours to years after initiation, and carries risk of airway compromise 1, 2.

Immediate Management Steps

Stop Entresto immediately and do not rechallenge - angioedema from ARNIs (angiotensin receptor-neprilysin inhibitors) is a serious adverse effect that can progress to complete airway obstruction 3, 2. The tongue swelling indicates oropharyngeal involvement, which can rapidly compromise the airway 1, 2.

Acute Assessment Required:

• Evaluate airway patency now - assess for difficulty breathing, stridor, or progressive swelling that may require emergency intubation or tracheotomy 2
• Administer acute treatment - corticosteroids, antihistamines, and epinephrine as needed for symptomatic management 1
• Monitor closely for 48-72 hours - angioedema typically resolves within this timeframe after drug discontinuation 1

Optimization of Heart Failure Regimen

Replace Entresto with ACE Inhibitor or ARB:

Transition to an ACE inhibitor (such as enalapril) or ARB (such as valsartan alone) after a 36-hour washout period from Entresto to allow neprilysin inhibition to clear 3. However, be aware:

• ACE inhibitors carry cross-reactivity risk - approximately 10-15% of patients with ARNI-induced angioedema will also react to ACE inhibitors 4
• ARBs are safer but not risk-free - angiotensin receptor blockers like losartan or valsartan alone have lower angioedema rates but cases still occur, suggesting mechanisms beyond bradykinin 4
• Start with ARB monotherapy first - given the angioedema history, an ARB (valsartan 40-80 mg twice daily, titrating to target 160 mg twice daily) is the safer initial choice over an ACE inhibitor 4

Maintain Current Beta-Blocker Therapy:

Continue carvedilol at current dose - beta-blockers are first-line therapy for heart failure and reduce mortality 5. Do not discontinue abruptly as this risks rebound myocardial ischemia and arrhythmias 5, 6.

• Target dose for carvedilol is 25-50 mg twice daily in heart failure 5
• If patient is not at target dose, consider gradual up-titration at 2-week intervals once angioedema resolves and new RAAS blocker is stable 5

Optimize Diuretic Therapy:

Continue furosemide (Lasix) for volume management - adjust dose based on daily weights and signs of congestion 5. Instruct patient to:

• Weigh daily after waking, before dressing, after voiding, before eating 5
• Increase diuretic dose if weight increases persistently (2 days) by 1.5-2.0 kg 5

Consider Adding Mineralocorticoid Receptor Antagonist:

If patient remains NYHA class III-IV despite optimal therapy, add spironolactone 25 mg daily (titrating to 50 mg daily) for additional mortality benefit 5, 6. Monitor:

• Serum potassium closely due to hyperkalemia risk when combined with ARB 6
• Renal function regularly 6

Critical Monitoring After Regimen Change

• Recheck blood chemistry 1-2 weeks after ARB initiation - monitor potassium, creatinine, and blood pressure 5
• Watch for recurrent angioedema - if tongue swelling recurs on ARB, consider non-RAAS alternatives (though this significantly limits guideline-directed medical therapy) 4
• Assess for signs of heart failure decompensation - Entresto was superior to enalapril in reducing cardiovascular death and hospitalization, so transitioning off may require closer monitoring 3

Common Pitfalls to Avoid

Do not restart Entresto or rechallenge - angioedema can recur more severely with repeat exposure 4, 2

Do not assume amlodipine or other medications are innocent - while less common, calcium channel blockers can rarely cause angioedema; review all medications if symptoms persist after Entresto discontinuation 7

Do not delay airway intervention if swelling progresses - angioedema can be fatal if airway obstruction occurs; have low threshold for emergency department evaluation 2

Do not stop beta-blocker during this transition - abrupt discontinuation carries significant cardiovascular risk 5, 6