In a patient with chronic kidney disease (creatinine 1.2 mg/dL) and heart failure with preserved ejection fraction (55 %), should I use sacubitril/valsartan (Entresto) or stick with an ACE inhibitor or ARB?

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Last updated: September 11, 2026 • View editorial policy

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Use an ACE Inhibitor or ARB, Not Entresto

For your patient with heart failure and an ejection fraction of 55% (HFpEF) and mild CKD (creatinine 1.2), stick with an ACE inhibitor or ARB rather than switching to Entresto (sacubitril/valsartan).

Why ACE/ARB is the Right Choice

Your patient has heart failure with preserved ejection fraction (HFpEF), not reduced ejection fraction. The evidence base for Entresto in HFpEF is fundamentally different—and weaker—than in HFrEF:

The Evidence Landscape

Entresto's FDA indication explicitly states benefits are "most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal" 1. With an EF of 55%, your patient falls outside this primary indication.

The PARAGON-HF trial, which tested Entresto in HFpEF patients (EF ≥45%), failed to meet its primary endpoint of reducing cardiovascular death or heart failure hospitalizations (rate ratio 0.87; 95% CI 0.75-1.01; P=0.06) 2. There was no mortality benefit whatsoever (HR 0.97) 2. While exploratory subgroup analyses suggested possible benefit in patients with EF 45-57% and in women, these are hypothesis-generating findings, not definitive evidence.

Guideline Recommendations Are Clear

The 2016 ESC guidelines give sacubitril/valsartan a Class I recommendation only for HFrEF patients who remain symptomatic despite optimal treatment with an ACE inhibitor, beta-blocker, and MRA 3. There is no equivalent recommendation for HFpEF.

The 2022 AHA/ACC/HFSA guidelines note that in PARAGON-HF, sacubitril/valsartan "did not achieve a significant reduction" in the primary endpoint for HFpEF 2. The Canadian guidelines similarly emphasize that sacubitril/valsartan's proven benefits are in patients with EF <40% and systolic dysfunction 4.

What About the Renal Function?

Your patient's creatinine of 1.2 mg/dL represents mild CKD. While Entresto does show renal benefits in HFpEF patients—including slower eGFR decline and reduced risk of renal events 5, 6—these renal advantages don't translate into the mortality or morbidity benefits that should drive your prescribing decision.

The renal data shows:

  • Entresto slowed eGFR decline compared to valsartan (-2.0 vs -2.7 mL/min/1.73m²/year) 5
  • Reduced composite renal outcomes (HR 0.50) 5
  • Similar renal protection in patients with and without diabetes 6

However, improved surrogate markers (eGFR, NT-proBNP) without mortality benefit is not sufficient justification for choosing a more expensive medication with a less robust evidence base in HFpEF.

The Practical Algorithm

For HFpEF (EF ≥50%):

  1. Start with ACE inhibitor or ARB for blood pressure control and comorbidity management 3, 4
  2. Add beta-blocker if indicated for rate control (especially with atrial fibrillation) or coronary disease
  3. Use diuretics for congestion management 3
  4. Treat underlying conditions: hypertension, diabetes, coronary disease, atrial fibrillation 2
  5. Consider SGLT2 inhibitors (emerging evidence in HFpEF)

Reserve Entresto for HFrEF (EF ≤40%):

  • Only after establishing tolerance to ACE inhibitor
  • In patients who remain symptomatic despite optimal medical therapy
  • As a replacement for ACE inhibitor, not in addition to it 3

Important Caveats

If you were considering Entresto based on the renal benefits alone, remember that:

  • ACE inhibitors and ARBs also provide renal protection in CKD 7
  • The KDIGO 2024 guidelines recommend ACE inhibitors or ARBs as first-line for CKD with albuminuria 7
  • Entresto costs significantly more than generic ACE inhibitors/ARBs
  • The renal composite outcome in PARAGON-HF, while improved, doesn't justify use when the primary cardiovascular outcome failed 5

Monitor closely if using any RAAS inhibitor:

  • Check creatinine and potassium within 2-4 weeks of initiation 7
  • Continue therapy unless creatinine rises >30% within 4 weeks 7
  • Hyperkalemia can often be managed without stopping the medication 7

Bottom line: Your patient's preserved ejection fraction and mild CKD make a standard ACE inhibitor or ARB the evidence-based choice. Entresto has not proven superior outcomes in this population and should be reserved for patients with reduced ejection fraction where the mortality benefit is established.

References

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.