What can replace Entresto (sacubitril/valsartan) in patients who cannot tolerate it?

Alternatives to Entresto (Sacubitril/Valsartan) for Patients Who Cannot Tolerate It

For patients who cannot tolerate Entresto (sacubitril/valsartan), angiotensin receptor blockers (ARBs) are the recommended first-line alternative, particularly valsartan at target doses of 160 mg twice daily. 1

Primary Alternatives

• Angiotensin Receptor Blockers (ARBs): Should be the first choice for patients who cannot tolerate Entresto but previously tolerated the ARB component 1

  • Valsartan (target dose 160 mg twice daily) has established efficacy for heart failure with reduced ejection fraction (HFrEF) 1
  • Candesartan has also demonstrated efficacy in HFrEF patients 1

• Angiotensin Converting Enzyme Inhibitors (ACE inhibitors): Remain a cornerstone therapy for HFrEF if ARBs are not tolerated 1

  • Should be titrated to target doses shown to reduce cardiovascular events in clinical trials 1
  • Provide mortality benefit across the clinical spectrum of HF severity 1

Approach to Replacement Based on Reason for Intolerance

If hypotension is the primary issue:

1. Assess and optimize volume status; consider reducing diuretic dose if no signs of congestion 1
2. Start with low-dose ACE inhibitor or ARB and up-titrate slowly with small increments 1
3. Consider adding medications with less impact on blood pressure first:
   • Start with SGLT2 inhibitors and mineralocorticoid receptor antagonists (MRAs) as they have minimal effect on blood pressure 1
   • Add beta-blockers if heart rate >70 bpm 1

If angioedema was the issue:

1. ARBs are recommended as they have a much lower incidence of angioedema than ACE inhibitors 1
2. Caution is still advised as some patients have developed angioedema with ARBs after ACE inhibitor-induced angioedema 1

If renal dysfunction was the issue:

1. Consider lower doses of ARBs with careful monitoring of renal function 2
2. Both ACE inhibitors and ARBs can cause similar renal effects in susceptible patients 2
3. Avoid in patients with bilateral renal artery stenosis 2

Medication Titration Strategy

• Begin with the lowest dose and gradually up-titrate every 1-2 weeks 1
• Monitor blood pressure, renal function, and serum potassium regularly 1, 3
• Target doses should match those proven effective in clinical trials 3
• For valsartan, aim for 160 mg twice daily as used in heart failure trials 3, 4

Common Pitfalls to Avoid

• Undertreatment with suboptimal dosing is common in heart failure management 3
• Failure to titrate medication to target doses is associated with suboptimal outcomes 3
• Unnecessary discontinuation of foundational HFrEF therapies due to asymptomatic low blood pressure 1
• Inadequate monitoring of renal function and potassium levels when initiating replacement therapy 1

Special Considerations

• For patients in sinus rhythm who cannot tolerate beta-blockers, ivabradine may be used for heart rate control 1
• For patients with atrial fibrillation and uncontrolled heart rate, digoxin may be considered 1
• Long-acting nitrates or ranolazine should be considered as add-on therapy for symptom control if needed 1

By following this structured approach to replacing Entresto, clinicians can maintain effective heart failure therapy while minimizing adverse effects in patients who cannot tolerate sacubitril/valsartan.