Treatment Benefits and Safety of Sacubitril/Valsartan Are Maintained Despite Early eGFR Decline

Many therapies used to treat heart failure (HF), including sacubitril/valsartan (SV), can result in early declines in the estimated glomerular filtration rate (eGFR). That can prompt physicians to discontinue the drug.

Researchers at Brigham and Women’s Hospital found that moderate eGFR decline when transitioning from a renin–angiotensin system inhibitor (RASi) to SV was not consistently associated with adverse outcomes. In addition, long-term benefits of SV were retained in patients with HF across a broad range of initial eGFR declines.

Muthiah Vaduganathan, MD, MPH, a cardiologist in the Division of Cardiovascular Medicine at the Brigham, Safia Chatur, MD, a research fellow in the Division, and colleagues published their findings in the Journal of the American College of Cardiology.


The team conducted post hoc analyses of two pivotal trials of SV: PARADIGM-HF, which compared SV with enalapril, and PARAGON-HF, which compared it with valsartan. Participants first enrolled in a RASi run-in period (target dose of enalapril or half-target dose of valsartan), followed by an SV run-in period (target dose in PARADIGM-HF and half-target dose in PARAGON-HF).

Patients were excluded during the run-in phase if eGFR declined to <30 mL/min/1.73 m2 (PARADIGM-HF) or <25 mL/min/1.73 m2 (PARAGON-HF) or by >35% between screening and randomization.

The primary outcome was the composite of cardiovascular death or first HF hospitalization (PARADIGM-HF) or the composite of total HF hospitalizations or death from CV causes (PARAGON-HF).

Early eGFR Decline

Most patients in the two trials had little to no change in eGFR upon initial exposure to RASi or sacubitril/valsartan:

RASi run-in

  • PARADIGM-HF: 49% of participants experienced no eGFR decline, 38% experienced a decline ≤15%, and 13% experienced a decline >15%
  • PARAGON-HF: 48%, 39%, and 13%, respectively

SV run-in

  • PARADIGM-HF: 52% of participants experienced no eGFR decline, 37% experienced a decline ≤15%, and 11% experienced a decline >15%
  • PARAGON-HF: 48%, 42%, and 10%, respectively

Recovery of eGFR

Most participants remaining in the study after SV run-in had at least partial recovery of eGFR. The median percent recovery from nadir to post-randomization week 16 was:

  • PARADIGM-HF: 50% of participants randomly assigned to SV vs. 53% of those assigned to enalapril (P=0.55)
  • PARAGON-HF: 46% of patients assigned to SV vs. 44% of those assigned to valsartan (P=0.76)

Recovery occurred quickly—within weeks—irrespective of the patient’s ejection fraction.

Other Key Findings

In both trials, the treatment benefit and safety of SV was consistent:

  • The treatment effect of SV relative to RASi was consistent whether or not participants experienced eGFR decline during the RASi run-in period
  • Safety outcomes and the rate of drug discontinuation caused by severe adverse events were unaffected by whether participants experienced eGFR decline during the SV run-in period
  • eGFR decline while patients were receiving SV did not significantly affect the development of the primary outcome

Guidance for the Clinic

Physicians often use previous tolerance to RASi to predict tolerance to SV. In contradiction to that standard practice, this study suggests moderately poor renal response with RASi alone should not dissuade a trial of SV because treatment benefit appears to be preserved even in that circumstance.

In addition, early eGFR changes during SV therapy should not deter its continuation or delay its up-titration.

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