Implications of Expanded FDA Labeling for Sacubitril/Valsartan

Quick Takes

  • The FDA expanded labeling for sacubitril/valsartan to patients with chronic HF and a lower-than-normal LVEF (now covering patients with HFmrEF and HFpEF).
  • This expanded labeling has the potential to make an additional 1.8 million HF patients eligible for sacubitril/valsartan therapy and prevent worsening HF events.
  • The real-world impact of this new labeling is still to be determined.

Study Questions:

In February 2021, the US Food and Drug Administration (FDA) expanded labeling for sacubitril/valsartan (SV) to patients with chronic heart failure (HF) and a left ventricular ejection fraction (LVEF) lower than normal (no defined cutoff). What are the implications of the expanded labeling, which allows for SV use at higher LVEF values?


Using data from the National Health and Nutrition Examination Survey (NHANES) and the Get With The Guidelines–Heart Failure (GWTG-HF) registry, an estimated number of patients newly eligible for SV use under the expanded FDA labeling was determined for various LVEF ranges (41-50%, 41-55%, 41-57%, and 41-60%). Data from the PARAGON-HF trial were used to estimate potential clinical endpoints and safety events in these newly eligible cohorts.


There were an estimated 4,682,098 adults in the US with chronic HF without a potential intolerance to SV. From this population, the following groups of potential newly eligible candidates for SV (based on various LVEF ranges) along with estimated clinical events were reported.

LVEF 41-50%:

  • 43,161 patients newly eligible
  • Estimated worsening HF events prevented: 69,268
  • Includes cardiovascular death, total HF hospitalizations, urgent HF visits

LVEF 41-55%:

  • 1,181,913 patients newly eligible
  • Estimated worsening HF events prevented: 161,941

LVEF 41-57%:

  • 1,317,618 patients newly eligible
  • Estimated worsening HF events prevented: 150,208

LVEF 41-60%:

  • 1,838,756 patients newly eligible
  • Estimated worsening HF events prevented: 182,592


The new FDA labeling for SV has the potential to significantly increase the population eligible for treatment and prevent many worsening HF events. The impact varies based on the definition of an abnormal LVEF.


Previously, the FDA labeling for SV was aimed at patients with LVEF of ≤40%. This expanded labeling represents a significant move to offer therapies targeted to HF patients with mid-range (HFmrEF) and preserved (HFpEF) LVEFs. While the PARAGON-HF trial did not meet its primary endpoint, the FDA made this recommendation based on a body of evidence that suggested potential benefit of SV in HF over a wide range of LVEFs. The new labeling does not specify a new LVEF cutoff, but rather suggests use in patients with lower-than-normal LVEF. The expected impact of this change will vary based on how prescribing providers interpret this messaging. As the authors of this work demonstrate, the potential impact of the new labeling is still great despite what range of LVEFs are used for the newly eligible patients but has the potential to reach 1.8 million patients and prevent an estimated 182,592 worsening HF events. It will be interesting to see what the real-world adoption of this expanded labeling is. Factors such as provider and patient preferences, insurance coverage, cost, and new HF therapeutics may reduce the overall impact.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure

Keywords: Aminobutyrates, Heart Failure, Hospitalization, Secondary Prevention, Stroke Volume, Tetrazoles, United States Food and Drug Administration, Valsartan, Ventricular Function, Left

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