FDA Panel Votes on Entresto for HF With Preserved Ejection Fraction

The recommendation was based on data from the double-blind, parallel-group, active-controlled phase 3 PARAGON-HF trial.

The Food and Drug Administration (FDA)’s Cardiovascular and Renal Drugs Advisory Committee voted in favor (12 to 1) of the use of Entresto® (sacubitril/valsartan; Novartis) in the treatment of patients with heart failure with preserved ejection fraction (HFpEF).

The recommendation was based on data from the double-blind, parallel-group, active-controlled phase 3 PARAGON-HF trial that compared the long-term efficacy and safety of sacubitril/valsartan to valsartan in 4822 patients with HFpEF. The primary end point was the composite of cardiovascular (CV) death and total (first and recurrent) heart failure (HF) hospitalizations.

The trial missed statistical significance for its composite primary end point (rate ratio [RR] 0.87; 95% CI, 0.75-1.01; P =.06), however a greater benefit was observed in certain predefined subgroups. Subgroup analyses showed a 22% relative reduction (RR 0.78; 95% CI, 0.64-0.95) in patients with an ejection fraction ≤57% (median) and a 27% relative reduction (RR 0.73; 95% CI, 0.59-0.90) in women. In a separate post-hoc analysis, the treatment effect of sacubitril/valsartan on total heart failure hospitalizations and cardiovascular death was observed to be greatest among HFpEF patients screened during or within 30 days of hospitalization.

Additional evidence of benefit from the PARAMOUNT and PARADIGM-HF trials was also evaluated by the panel. In meeting documents, it was noted that “[Novartis] combined data from the PARAGON-HF trial with data from the PARADIGM-HF trial that formed the basis of the HFrEF indication, to establish ‘totality of evidence’ to support an approval for HF within a range of LVEFs that overlap HFrEF and the lower end of HFpEF.”

In exploratory secondary end point analyses, sacubitril/valsartan-treated patients reported less worsening in quality of life based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at 8 months compared with valsartan, along with a reduction in the risk of worsening renal function. The sacubitril/valsartan treatment arm also experienced a more favorable change in the New York Heart Association (NYHA) class compared with valsartan. There was no difference in all-cause mortality between the treatment arms.

Currently, there are no approved treatments for HFpEF; a decision on the supplemental New Drug Application by the FDA is expected in the first quarter of 2021. Although not bound by the committees’ recommendations, the FDA does take them into consideration when making decisions on approval.

Entresto is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker and is FDA-approved to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It is also indicated to treat symptomatic heart failure with systemic left ventricular systolic dysfunction in children aged 1 year and older.


1.      Novartis announces positive FDA Advisory Committee recommendation for use of Entresto® to treat patients with HFpEF. [press release]. December 15, 2020.

2.      Cardiovascular and Renal Drugs Advisory Committee meeting: FDA briefing document. https://www.fda.gov/media/144377/download. December 15, 2020.