Is Entresto (sacubitril/valsartan) more effective than amlodipine for increasing ejection fraction in patients with heart failure with reduced ejection fraction (HFrEF)?

Entresto (Sacubitril/Valsartan) vs. Amlodipine for Increasing Ejection Fraction in Heart Failure

Entresto (sacubitril/valsartan) is significantly more effective than amlodipine for increasing ejection fraction in patients with heart failure with reduced ejection fraction (HFrEF). 1, 2

Evidence Supporting Entresto for Improving Ejection Fraction

Mechanism of Action and Clinical Evidence

• Entresto works through dual mechanisms:

  • Angiotensin receptor blockade via valsartan
  • Neprilysin inhibition via sacubitril, which prevents breakdown of beneficial peptides 3

• In a clinical study of 794 patients with HFrEF, Entresto demonstrated significant improvement in ejection fraction across all patient groups regardless of heart failure duration:

  • 12.2% absolute LVEF improvement in patients with HF <12 months
  • 6.9-8.6% absolute LVEF improvement in patients with longer-standing HF 2

• Another study showed that Entresto significantly improved left ventricular function parameters compared to standard therapy, including:

  • Improved LVEF
  • Reduced LVMI (left ventricular mass index)
  • Improved diastolic function parameters (E/E' ratio, E/A ratio) 4

Guideline Recommendations

The 2022 AHA/ACC/HFSA Heart Failure Guidelines strongly support the use of Entresto:

• Sacubitril/valsartan is recommended as a replacement for ACE inhibitors or ARBs in patients with HFrEF to reduce the risk of HF hospitalization and death (Class I recommendation) 1

• For patients with HFmrEF (LVEF 41-49%), a subgroup analysis of the PARAGON-HF trial showed benefit of sacubitril/valsartan versus valsartan alone (rate ratio 0.78; 95% CI, 0.64-0.95) 1

• The ESC guidelines also recommend sacubitril/valsartan instead of ACEIs to reduce the risk of HF hospitalization and death in patients with HFrEF who remain symptomatic despite treatment with ACEIs, beta-blockers, and MRAs 1

Amlodipine in Heart Failure

• Amlodipine is a calcium channel blocker primarily used for hypertension management
• It is not included in any of the major heart failure guidelines as a medication to improve ejection fraction 1, 5
• Calcium channel blockers are not part of guideline-directed medical therapy (GDMT) for HFrEF
• No evidence in the guidelines supports amlodipine for improving ejection fraction

Practical Approach to Medication Selection

For patients with HFrEF requiring treatment to improve ejection fraction:

1. First-line therapies should include:

   • SGLT2 inhibitors (empagliflozin, dapagliflozin)
   • Beta-blockers (carvedilol, metoprolol succinate, bisoprolol)
   • Mineralocorticoid receptor antagonists (spironolactone, eplerenone)
   • ACEIs/ARBs or preferably Entresto 1, 5

2. When to use Entresto:

   • As replacement for ACEIs/ARBs in symptomatic HFrEF patients
   • Can be used in both newly diagnosed and long-standing HFrEF 2
   • Should be initiated at low dose (24/26 mg twice daily) and titrated to target dose (97/103 mg twice daily) 6

3. Monitoring during Entresto therapy:

   • Blood pressure (watch for hypotension)
   • Renal function and electrolytes
   • Clinical response including symptoms and ejection fraction 6

Common Pitfalls to Avoid

1. Inappropriate medication selection: Using amlodipine instead of evidence-based GDMT for improving ejection fraction

2. Inadequate dosing: Failing to titrate Entresto to target doses (97/103 mg twice daily) when tolerated

3. Contraindications to Entresto:

   • History of angioedema
   • Concomitant ACE inhibitor use (requires 36-hour washout)
   • Pregnancy
   • Severe hepatic impairment

4. Monitoring failures: Not checking renal function and potassium when initiating or titrating Entresto

Conclusion

Based on the most recent and highest quality evidence, Entresto (sacubitril/valsartan) has demonstrated significant benefits for improving ejection fraction in patients with HFrEF, while amlodipine has no established role for this purpose. The clinical evidence and guideline recommendations strongly favor Entresto as part of comprehensive GDMT for patients with reduced ejection fraction.