What are alternative treatments for patients who cannot tolerate Entresto (sacubitril/valsartan)?

Alternative Treatments for Patients Who Cannot Tolerate Entresto

For patients who cannot tolerate Entresto (sacubitril/valsartan), angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are the recommended alternative treatments for heart failure with reduced ejection fraction (HFrEF). 1

First-Line Alternatives

ACE Inhibitors

• Mechanism: Inhibit the conversion of angiotensin I to angiotensin II
• Benefits: Reduce mortality, hospitalization, and heart failure progression
• Examples: Enalapril, lisinopril, captopril, ramipril
• Dosing: Start at low doses and titrate upward to target doses shown to reduce cardiovascular events in clinical trials 1
• Contraindications: History of angioedema with previous ACEI use, bilateral renal artery stenosis

ARBs

• Mechanism: Block angiotensin II receptors
• Benefits: Similar benefits to ACEIs in reducing heart failure hospitalization
• Examples: Valsartan, candesartan, losartan
• Dosing: Higher doses provide better outcomes (e.g., losartan 150 mg daily superior to 50 mg daily) 1
• Key evidence: CHARM-Alternative trial showed candesartan reduced cardiovascular death or HF hospitalization by 23% in ACEI-intolerant patients 1

Selection Algorithm

1. If Entresto intolerance is due to angioedema:

   • Avoid ACEIs (cross-reactivity risk)
   • Use ARB as first choice 1

2. If Entresto intolerance is due to hypotension:

   • Start with low-dose ACEI or ARB
   • Titrate slowly based on blood pressure response
   • Consider discontinuing other antihypertensive medications if possible 1

3. If Entresto intolerance is due to renal dysfunction or hyperkalemia:

   • Consider lower doses of ACEI or ARB
   • Monitor renal function and potassium levels closely
   • May need to add diuretics to manage volume status 1

Evidence-Based Recommendations

The 2017 ACC/AHA/HFSA guidelines specifically state: "For those patients for whom an ACE inhibitor or ARNI is inappropriate, use of an ARB remains advised." 1

The European Society of Cardiology guidelines note that ARBs are reasonable alternatives to ACEIs in patients with HFrEF who are unable to tolerate ACEIs, with the CHARM-Alternative trial showing significant benefits in this population 1.

Important Considerations

• Washout period: When switching from an ARNI to an ACEI, a 36-hour washout period is required to avoid angioedema risk. No washout is needed when switching to an ARB 2

• Dosing targets: Aim for target doses shown to be effective in clinical trials rather than lower doses 1

• Monitoring: Check blood pressure, renal function, and potassium levels within 1-2 weeks after starting or increasing the dose 1

• Common pitfall: Using suboptimal doses of ACEIs or ARBs. Evidence shows higher doses provide better outcomes, as demonstrated in the HEAAL and ATLAS trials 1

• Caution: Even with ARBs, there is a small risk of angioedema in patients who previously experienced angioedema with ACEIs 1

Additional Therapy Considerations

For optimal management of HFrEF, patients should also receive:

• Beta-blockers
• Mineralocorticoid receptor antagonists (spironolactone or eplerenone)
• SGLT2 inhibitors (newer addition to guideline-directed medical therapy)

These medications should be continued or initiated regardless of which RAAS inhibitor (ACEI, ARB, or ARNI) is used, as they provide complementary benefits in reducing morbidity and mortality.