FDA Panel Votes on Expanded Use of Heart Failure Drug


An FDA panel voted to recommend the expanded use of sacubitril/valsartan (Entresto; Novartis).

Heart failure medication

An FDA panel voted to recommend the expanded use of sacubitril/valsartan (Entresto; Novartis) for patients with heart failure with preserved ejection fraction (HFpEF).1

The FDA Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted 12 to 1 in favor of approving the drug, which is already indicated for patients with heart failure with reduced ejection fraction (HFrEF), to expand its use for patients with HFpEF.1

There are currently no approved therapies for HFpEF to address the prevention of HF hospitalizations and urgent visits. Sacubitril/valsartan was first approved by the FDA in 2015 for patients with New York Association class II through IV heart failure, to reduce the risk of both cardiovascular (CV) death and hospitalization. Subsequently, the treatment received approval for indications for patients with HFrEF and those 1 year or older with symptomatic HF with systemic left ventricular systolic dysfunction.1,2

The panel’s recommendation was based on the totality of efficacy and safety analyses, including findings presented from a pre-specified subgroup analysis of the PARAGON-HF phase 3 study and additional evidence from the PARAMOUNT and PARADIGM-HF trials.2

PARAGON-HF fell short in meeting its primary end point in reducing total hospitalization and CV death in patients with HFpEF; however, the data did suggest a benefit in some patient groups. Although approval under this circumstance is unusual, the panel indicated that it is not unprecedented.2

As such, the findings from PARAGON-HF suggested benefit in patients with ejection fraction toward the lower end of the range studied, or closer to the range for patients with HFrEF.3

In PARAGON-HF, a total of 4822 patients were randomly assigned to sacubitril/valsartan or valsartan. Patients in the study were required to have signs and symptoms of HF, a left ventricular ejection fraction (LEVF) of 45% or greater, evidence of natriuretic peptide elevation, and structural heart disease. The median follow-up was 34 months.3 

According to the results, the rate ratio for the primary end point was 0.87 (95% confidence interval [CI] 0.75-1.01; p=0.059), which was just short of statistical significance and driven by a decline in HF hospitalization with no effect on CV death or all-cause mortality. However, the results indicated greater benefit in patients with ejection fraction below the median of 57%, with a 22% reduction (rate ratio 0.78; 95% CI 0.64-0.95) and in women, with a 28% reduction (rate ratio 0.73; 95% CI 0.59-0.90) in the primary end point.3

“The prevalence of HF with LVEF ≥ 45% is increasing in the US, with increasing life expectancy, and epidemics of metabolic syndrome and [diabetes mellitus],” the FDA briefing document states.2 “The overall benefit-risk considerations may support approval of sacubitril/valsartan to treat patients with HF with LVEF ≥ 45%.”

In response to the Committee’s decision, Scott Solomon, MD, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, and PARAGON-HF Executive Committee Co-Chair, said, “Managing HFpEF has historically been a clinical and scientific challenge due to the heterogeneity of the condition. Today’s vote represents much needed progress in this area of unmet need and is a positive step toward bringing a potential therapy to millions of patients suffering from this type of heart failure.”1

The FDA is expected to make a decision on the supplemental new drug application in the first quarter of 2021.1


  1. Novartis announces positive FDA Advisory Committee recommendation for use of Entresto to treat patients with HFpEF. News release. Novartis; December 16, 2020. Accessed December 16, 2020. https://www.novartis.com/news/media-releases/novartis-announces-positive-fda-advisory-committee-recommendation-use-entresto-treat-patients-hfpef
  2. FDA. Cardiovascular and Renal Drugs Advisory Committee Meeting, December 15, 2020. FDA briefing document. December 15, 2020. Accessed December 16, 2020. https://www.fda.gov/media/144377/download
  3. PARAGON-HF misses endpoint in preserved heart failure, but benefit noted in some patients. News release. European Society of Cardiology; September 1, 2019. Accessed December 16, 2020. https://www.escardio.org/The-ESC/Press-Office/Press-releases/paragon-hf-misses-endpoint-in-preserved-heart-failure-but-benefit-noted-in-some-patients
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