Sacubitril/Valsartan in Patients With Heart Failure and Deterioration in eGFR to <30 mL/min/1.73 m2

JACC Heart Fail. 2024 Oct;12(10):1692-1703. doi: 10.1016/j.jchf.2024.03.014. Epub 2024 Jun 5.

Abstract

Background: Sacubitril/valsartan is a foundational therapy for patients with heart failure. Although current U.S. Food and Drug Administration labeling does not provide guidance regarding initiation or continuation of sacubitril/valsartan in patients with worsening kidney function, guidelines identify estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 as a contraindication to therapy.

Objectives: This study aims to assess the safety and efficacy of continuing sacubitril/valsartan in patients with deterioration of kidney function below an eGFR of 30 mL/min/1.73 m2.

Methods: The association between a deterioration in eGFR <30 mL/min/1.73 m2, efficacy and safety outcomes, and treatment with sacubitril/valsartan vs renin-angiotensin system inhibitor were evaluated using time updated Cox models in a post hoc parallel trial analyses of PARADIGM-HF and PARAGON-HF.

Results: Among 8,346 randomized patients in PARADIGM-HF and 4,746 in PARAGON-HF, 691 (8.3%) and 613 (12.9%), respectively, had an eGFR <30 mL/min/1.73 m2 at least once in follow-up. Patients experiencing such deterioration were at higher risk of the primary outcome in both PARADIGM-HF and PARAGON-HF. However, the incidence of the primary outcome remained lower with sacubitril/valsartan vs renin-angiotensin system inhibitor, regardless of deterioration in kidney function in both PARADIGM-HF (Pinteraction = 0.50) and PARAGON-HF (Pinteraction = 0.64). Rates of key safety outcomes were higher among patients experiencing eGFR deterioration; however, rates were similar between treatment groups including among those who remained on treatment.

Conclusions: Patients experiencing deterioration of kidney function to a value below eGFR 30 mL/min/1.73 m2 faced high risk of cardiovascular and kidney disease outcomes. Continuation of sacubitril/valsartan was associated with persistent clinical benefit and no incremental safety risk. These data support continuation of sacubitril/valsartan for heart failure treatment even when eGFR declines below this threshold (PARADIGM-HF [Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure], NCT01035255; and PARAGON-HF [Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction], NCT01920711).

Keywords: angiotensin receptor-neprilysin inhibitor; heart failure; kidney function; sacubitril; valsartan.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aminobutyrates* / therapeutic use
  • Angiotensin Receptor Antagonists* / therapeutic use
  • Biphenyl Compounds*
  • Drug Combinations*
  • Female
  • Glomerular Filtration Rate*
  • Heart Failure* / drug therapy
  • Heart Failure* / physiopathology
  • Humans
  • Male
  • Middle Aged
  • Tetrazoles* / adverse effects
  • Tetrazoles* / therapeutic use
  • Treatment Outcome
  • Valsartan*

Substances

  • Aminobutyrates
  • Biphenyl Compounds
  • Valsartan
  • sacubitril and valsartan sodium hydrate drug combination
  • Drug Combinations
  • Angiotensin Receptor Antagonists
  • Tetrazoles

Associated data

  • ClinicalTrials.gov/NCT01920711