Does Entresto (sacubitril/valsartan) worsen Acute Kidney Injury (AKI)?

Does Entresto (Sacubitril/Valsartan) Worsen Acute Kidney Injury?

Entresto (sacubitril/valsartan) does not worsen acute kidney injury (AKI) compared to standard renin-angiotensin system inhibitors, and may even provide renal protective effects in certain populations. 1

Mechanism of Action and Kidney Effects

Entresto is a combination medication containing:

• Sacubitril (neprilysin inhibitor)
• Valsartan (angiotensin receptor blocker)

Like other RAAS inhibitors, Entresto can affect kidney function through several mechanisms:

• It can cause an initial, usually reversible decrease in eGFR
• It alters renal hemodynamics by affecting the afferent and efferent arterioles
• It may reduce intravascular volume through its natriuretic effects

Evidence on Entresto and AKI Risk

The most recent and highest quality evidence from a large cohort study of 27,166 Medicare patients with heart failure with reduced ejection fraction (HFrEF) found that:

• The 180-day cumulative incidence of AKI hospitalization was 2.7% for both Entresto and standard RAS inhibitor users
• Hazard ratio for AKI comparing Entresto with RAS inhibitors was 0.91 (95% CI: 0.72-1.16)
• There was no increased risk of AKI with Entresto compared to traditional RAS inhibitors 1

Another study in patients with HFrEF and chronic kidney disease showed that Entresto had no higher incidence of AKI compared to ACE inhibitors/ARBs, while demonstrating lower all-cause mortality in CKD patients 2.

Special Considerations During AKI

While Entresto does not appear to worsen AKI risk compared to other RAAS inhibitors, general principles for managing RAAS inhibitors during AKI should be followed:

1. During acute illness with volume depletion:

   • Consider temporarily holding Entresto as part of "sick day protocols" 3
   • Resume once renal function has returned to baseline or stabilized

2. Monitoring recommendations:

   • Regular assessment of renal function and potassium levels
   • Avoid concurrent nephrotoxic medications (especially NSAIDs) 4
   • Monitor for hyperkalemia, which is listed as a common side effect 4

FDA Label Information

The FDA label for Entresto acknowledges:

• "Kidney problems are common during treatment with sacubitril and valsartan tablets and can be serious and can lead to kidney failure" 4
• "Your doctor will check your kidney function during your treatment with sacubitril and valsartan tablets" 4

However, this warning is similar to those for other RAAS inhibitors and reflects the need for monitoring rather than an increased risk compared to alternatives.

Precautions and Risk Factors

Certain conditions may increase risk of kidney problems with Entresto:

• Volume depletion
• Concurrent diuretic use
• Pre-existing kidney disease
• Use with NSAIDs (especially in elderly or volume-depleted patients) 4

Conclusion

Current evidence indicates that Entresto does not worsen AKI compared to traditional RAAS inhibitors. In fact, some studies suggest potential renoprotective effects 5, 6. However, like all RAAS inhibitors, appropriate monitoring of kidney function and careful patient selection remain important to minimize risk.