What are the alternatives to Entresto (sacubitril/valsartan) 49-51 for patients who cannot tolerate it?

Alternatives to Entresto (Sacubitril/Valsartan) 49-51 mg

For patients who cannot tolerate Entresto, angiotensin receptor blockers (ARBs)—specifically valsartan 160 mg twice daily or candesartan 32 mg once daily—are the first-line alternatives, followed by ACE inhibitors if ARBs are also not tolerated. 1

Primary Alternative: ARBs

ARBs are recommended as the preferred first-line replacement when Entresto cannot be tolerated, as they provide established mortality and morbidity benefits in heart failure with reduced ejection fraction (HFrEF). 1

Specific ARB Options and Dosing:

• Valsartan: Start at 40 mg twice daily, uptitrate to 80 mg twice daily, then target 160 mg twice daily (320 mg total daily dose). 1, 2
• Candesartan: Start at 4-8 mg once daily, uptitrate to target dose of 32 mg once daily. 2
• Both agents reduce cardiovascular death and heart failure hospitalization by 17-24% when added to standard therapy. 2

Monitoring Requirements:

• Check renal function and serum potassium within 1 week of initiation. 2, 1
• Recheck at 1,3, and 6 months after achieving maintenance dose, then every 6 months. 2
• Monitor blood pressure at 2-4 weeks to assess response. 1

Secondary Alternative: ACE Inhibitors

If ARBs are also not tolerated, ACE inhibitors remain a cornerstone therapy and should be titrated to target doses proven in clinical trials. 1

• ACE inhibitors provide mortality benefit across all severity levels of heart failure. 1
• They reduce infarct expansion, prevent left ventricular remodeling, and decrease recurrent MI and sudden death. 2
• Target evidence-based doses (e.g., enalapril 10-20 mg twice daily, lisinopril 20-40 mg once daily). 2

Key Contraindication:

• Never combine ACE inhibitors with ARBs or Entresto due to increased risk of angioedema, hyperkalemia, hypotension, and renal dysfunction. 2, 1

Approach Based on Reason for Intolerance

If Hypotension is the Issue:

• Optimize volume status first before initiating replacement therapy. 1
• Start with the lowest dose of ACE inhibitor or ARB and uptitrate slowly with small increments every 1-2 weeks. 1
• Add SGLT2 inhibitors and mineralocorticoid receptor antagonists (MRAs) first, as they have minimal blood pressure effects. 1
• Add beta-blockers if heart rate >70 bpm after other agents are optimized. 1

If Angioedema Occurred:

• ARBs are strongly recommended as they have a much lower incidence of angioedema compared to ACE inhibitors. 1
• Avoid all ACE inhibitors permanently if angioedema occurred with Entresto (which contains valsartan, an ARB component). 2

If Renal Dysfunction or Hyperkalemia:

• Avoid initiating replacement therapy if potassium >5.0 mEq/L or creatinine >2.5 mg/dL (men) or >2.0 mg/dL (women). 2, 1
• Consider hydralazine-isosorbide dinitrate (H-ISDN) combination as an alternative if both ACE inhibitors and ARBs are contraindicated. 2

Third-Line Alternative: Hydralazine-Isosorbide Dinitrate

H-ISDN combination may be used as an alternative if there is intolerance to both ACE inhibitors and ARBs. 2

• This combination has demonstrated mortality benefit in patients not receiving ACE inhibitors or beta-blockers. 2
• Evidence is strongest in patients of African-American descent. 2
• Common side effects include headaches and gastrointestinal distress, which can limit long-term adherence. 2

Critical Pitfalls to Avoid

• Do not underdose replacement therapy: Failure to titrate to target doses proven in clinical trials is associated with suboptimal outcomes. 1
• Do not discontinue therapy for asymptomatic low blood pressure: Only symptomatic hypotension warrants dose adjustment. 1
• Do not combine ACE inhibitors with ARBs or aldosterone antagonists: This increases adverse events without improving survival. 2
• Do not neglect serial monitoring: Inadequate monitoring of renal function and potassium can lead to dangerous complications. 1

Additional Considerations

• For patients who cannot tolerate beta-blockers (if also being replaced), ivabradine may be used for heart rate control in sinus rhythm. 2, 1
• Aldosterone antagonists (spironolactone or eplerenone) should be continued or added if not already prescribed, as they provide additional mortality benefit. 2
• SGLT2 inhibitors are now foundational therapy for HFrEF and should be initiated regardless of which renin-angiotensin system blocker is used. 1