Is using Entresto (Sacubitril/Valsartan) more appropriate than using Valsartan and Carvedilol for heart failure?

From the Guidelines

For patients with heart failure with reduced ejection fraction (HFrEF), using Entresto (Sacubitril/Valsartan) is more appropriate than using Valsartan and Carvedilol due to its superior outcomes in reducing cardiovascular mortality and heart failure hospitalizations. This recommendation is based on the most recent and highest quality evidence from a large randomized clinical trial, which demonstrated that an ARNI (valsartan/sacubitril) reduced the composite endpoint of cardiovascular death or heart failure hospitalization significantly, by 20% 1. The benefit of Entresto was seen to a similar extent for both death and heart failure hospitalization and was consistent across subgroups.

Key Considerations

• Entresto has a dual mechanism of action, with valsartan blocking angiotensin II receptors and sacubitril inhibiting neprilysin, preventing the breakdown of beneficial peptides that promote vasodilation and sodium excretion.
• The typical starting dose of Entresto is 49/51 mg twice daily, titrated to a target of 97/103 mg twice daily as tolerated.
• Carvedilol, a beta-blocker, should still be used alongside Entresto as they work through different mechanisms.
• When initiating Entresto, patients should discontinue ACE inhibitors at least 36 hours before starting to avoid angioedema risk.
• Blood pressure, potassium, and renal function should be monitored regularly.

Patient Selection

• The benefit of Entresto is well established for patients with HFrEF, but its use in patients with heart failure with preserved ejection fraction (HFpEF) is less clear, and the traditional combination of Valsartan and Carvedilol may be appropriate in some cases.
• The choice between Entresto and a combination of Valsartan and Carvedilol depends on the specific heart failure presentation and individual patient characteristics. As supported by additional clinical trial evidence, meta-analyses, and observational clinical effectiveness studies 1, Entresto is a preferred option for reducing mortality and morbidity in patients with HFrEF.

From the FDA Drug Label

The primary objective of PARADIGM-HF was to determine whether sacubitril and valsartan, a combination of sacubitril and an RAS inhibitor (valsartan), was superior to an RAS inhibitor (enalapril) alone in reducing the risk of the combined endpoint of cardiovascular (CV) death or hospitalization for heart failure (HF) PARADIGM-HF demonstrated that sacubitril and valsartan, an combination of sacubitril and a RAS inhibitor (valsartan), was superior to a RAS inhibitor (enalapril), in reducing the risk of the combined endpoint of cardiovascular death or hospitalization for heart failure, based on a time-to-event analysis (hazard ratio [HR] 0.8; 95% confidence interval [CI], 0.73,0.87, p < 0. 0001)

The FDA drug label does not directly compare Entresto (Sacubitril/Valsartan) to Valsartan and Carvedilol for heart failure. However, it does show that Sacubitril and Valsartan is superior to Enalapril in reducing the risk of cardiovascular death or hospitalization for heart failure.

• Key points:
  • Sacubitril and Valsartan was compared to Enalapril, not Valsartan and Carvedilol.
  • The study showed a reduction in both cardiovascular death and heart failure hospitalization with Sacubitril and Valsartan compared to Enalapril.
  • Most patients in the study were taking beta-blockers (94%), which includes Carvedilol.
  • The label does not provide a direct comparison to make a conclusion about the appropriateness of using Entresto (Sacubitril/Valsartan) versus Valsartan and Carvedilol for heart failure 2.

From the Research

Comparison of Entresto (Sacubitril/Valsartan) and Valsartan with Carvedilol for Heart Failure

• The efficacy and safety of sacubitril/valsartan compared to valsartan in patients with heart failure and mildly reduced and preserved ejection fractions were evaluated in a systematic review and meta-analysis of randomized controlled trials 3.
• The study found that sacubitril/valsartan was superior to valsartan in some key heart failure outcomes, such as the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and the New York Heart Association class.
• However, there was no additional benefit with sacubitril/valsartan compared to valsartan for the outcomes of cardiovascular death and all-cause mortality.
• Another study compared sacubitril/valsartan to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in managing heart failure with preserved ejection fraction (HFpEF) and found that sacubitril/valsartan substantially reduced heart failure hospitalization rates compared to ACEIs and ARBs 4.
• A review of the efficacy and safety of sacubitril/valsartan in heart failure patients found that it was effective and safe in the treatment of heart failure with reduced ejection fraction (HFrEF) patients, but had little benefit in HFpEF patients 5.
• A study comparing sacubitril/valsartan to the angiotensin converting enzyme (ACE) inhibitor enalapril in the treatment of chronic heart failure with reduced ejection fraction found that sacubitril/valsartan reduced the incidence of death from cardiovascular causes or first hospitalization for worsening heart failure significantly more than enalapril 6.
• There is no direct comparison between sacubitril/valsartan and the combination of valsartan and carvedilol in the provided studies, but the available evidence suggests that sacubitril/valsartan may be a more effective treatment option for heart failure patients compared to traditional therapies 3, 7, 4, 5, 6.

Key Findings

• Sacubitril/valsartan is superior to valsartan in some key heart failure outcomes.
• Sacubitril/valsartan substantially reduces heart failure hospitalization rates compared to ACEIs and ARBs.
• Sacubitril/valsartan is effective and safe in the treatment of HFrEF patients.
• Sacubitril/valsartan may be a more effective treatment option for heart failure patients compared to traditional therapies.

Safety Considerations

• Sacubitril/valsartan is associated with a higher risk of hypotension compared to valsartan and ACEIs/ARBs.
• Sacubitril/valsartan does not show an increased risk of hyperkalemia or worsening renal function compared to valsartan.