Physicians' Academy for Cardiovascular Education

CV and kidney outcomes with ARNI in HFpEF independent of MRA background use

This subanalysis of PARAGON-HF showed that efficacy outcomes with sacubitril/valsartan compared to valsartan were independent of MRA use in patients with HFpEF.

Literature - Jering KS, Zannad F, Claggett B, et al. - JACC Heart Fail. 2021;9:13-24. doi: 10.1016/j.jchf.2020.08.014.

Introduction and methods

Patients with HFpEF have limited options for evidence-based treatment and management focuses on comorbid conditions. Current guidelines recommend the consideration of mineralocorticoid receptor antagonists (MRAs) in addition to an ARB, such as valsartan, in selected HFpEF patients [1]. Since resistant hypertension is common in patients with HFpEF, the MRA spironolactone is frequently used for blood pressure control [2,3].

The PARAGON-HF trial (Prospective Comparison of ARNI with ARB Global Outcomes in HF with preserved Ejection Fraction) compared the effects of sacubitril/valsartan with valsartan on CV and renal outcomes in patients with HFpEF. This trial just missed significance for the primary endpoint CV death and HF hospitalization, but a significant lowering of the prespecified renal composite endpoint was observed with sacubitril/valsartan compared with valsartan [4]. The efficacy and safety of sacubitril/valsartan in combination with an MRA in patients with HFpEF has not been evaluated yet.

This prespecified subanalysis of the PARAGON-HF trial assessed CV and renal outcomes and safety of sacubitril/valsartan compared to valsartan in patients with HFpEF according to MRA background.

Patients (≥50 years) with symptomatic HF (New York Heart Association [NYHA] functional classes II-IV), LVEF ≥45%, structural heart disease, need for diuretics, and elevated natriuretic peptides in the presence (n=1,239) or absence (n=3,557) of an MRA were included in the PARAGON-HF study. The primary endpoint was a composite of total (first and recurrent) hospitalization for HF and CV death. Secondary outcomes included a renal composite outcome of ≥50% decrease in eGFR, development of end-stage renal disease, or renal death The cardiorenal composite outcome was defined as first hospitalization for HF, CV death, ≥50% decrease in eGFR, development of end-stage renal disease, or renal death. Additional analysis included the slope of the change in eGFR during treatment (till week 192). Hyperkalemia (potassium >5.5 mmol/L) and severe hyperkalemia (potassium >6.0 mmol/L) were assessed as safety outcomes. Patients in this study were stratified by MRA treatment at baseline and treatment effects of sacubitril/valsartan were compared to valsartan.

Main results


This subanalysis of the PARAGON-HF trial showed that the clinical efficacy of sacubitril/valsartan compared to valsartan for predefined CV and renal composite outcomes were independent of MRA background use in patients with HFpEF. Moreover, eGFR decline was more attenuated over time in patients with sacubitril/valsartan compared to valsartan. This renal treatment effect was most prominent among MRA users.

The authors suggest that a combination therapy with sacubitril/valsartan and MRA could add possible beneficial value to patients with HFpEF.


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