Angiotensin-Neprilysin Inhibition in Patients With Mildly Reduced or Preserved Ejection Fraction and Worsening Heart Failure

J Am Coll Cardiol. 2023 Jul 4;82(1):1-12. doi: 10.1016/j.jacc.2023.04.019. Epub 2023 May 21.


Background: U.S. guidelines recommend consideration of sacubitril/valsartan in chronic heart failure (HF) and mildly reduced or preserved ejection fraction (EF). Whether initiation is safe and effective in EF >40% after a worsening heart failure (WHF) event is unknown.

Objectives: PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF) assessed sacubitril/valsartan vs valsartan in EF >40% following a recent WHF event.

Methods: PARAGLIDE-HF is a double-blind, randomized controlled trial of sacubitril/valsartan vs valsartan in patients with EF >40% enrolled within 30 days of a WHF event. The primary endpoint was time-averaged proportional change in amino terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through Weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: 1) cardiovascular death; 2) HF hospitalizations; 3) urgent HF visits; and 4) change in NT-proBNP.

Results: In 466 patients (233 sacubitril/valsartan; 233 valsartan), time-averaged reduction in the NT-proBNP was greater with sacubitril/valsartan (ratio of change: 0.85; 95% CI: 0.73-0.999; P = 0.049). The hierarchical outcome favored sacubitril/valsartan but was not significant (unmatched win ratio: 1.19; 95% CI: 0.93-1.52; P = 0.16). Sacubitril/valsartan reduced worsening renal function (OR: 0.61; 95% CI: 0.40-0.93) but increased symptomatic hypotension (OR: 1.73; 95% CI: 1.09-2.76). There was evidence of a larger treatment effect in the subgroup with EF ≤60% for NT-proBNP change (0.78; 95% CI: 0.61-0.98) and the hierarchical outcome (win ratio: 1.46; 95% CI: 1.09-1.95).

Conclusions: Among patients with EF >40% stabilized after WHF, sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared with valsartan alone, despite more symptomatic hypotension. (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF; NCT03988634).

Keywords: HFmrEF; acute decompensated HFpEF; clinical outcomes; natriuretic peptides; sacubitril/valsartan.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobutyrates / pharmacology
  • Aminobutyrates / therapeutic use
  • Angiotensin Receptor Antagonists / pharmacology
  • Angiotensin Receptor Antagonists / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Angiotensins / pharmacology
  • Angiotensins / therapeutic use
  • Biphenyl Compounds / therapeutic use
  • Drug Combinations
  • Heart Failure*
  • Humans
  • Hypotension* / chemically induced
  • Hypotension* / drug therapy
  • Neprilysin / therapeutic use
  • Stroke Volume
  • Tetrazoles / pharmacology
  • Tetrazoles / therapeutic use
  • Valsartan / therapeutic use


  • sacubitril
  • Neprilysin
  • Angiotensins
  • Angiotensin Receptor Antagonists
  • Tetrazoles
  • Angiotensin-Converting Enzyme Inhibitors
  • Valsartan
  • Aminobutyrates
  • Biphenyl Compounds
  • Drug Combinations

Associated data