Expanded FDA Label Increases Sacubitril/Valsartan Eligibility in Heart Failure Care


The potential number of adults projected to be newly eligible for treatment had a range from 643,161 (LVEF, 41% - 50%) to 1,838,756 (LVEF, 41% - 60%).

Scott D. Solomon, MD

Scott D. Solomon, MD

Earlier this year, the US Food and Drug Administration (FDA) expanded the label for sacubitril/valsartan in patients with chronic heart failure (HF) with left ventricular ejection fraction (LVEF) lower than normal.

As a result, investigators in a recent study projected the number of newly eligible treatment candidates for sacubitril/valsartan under the expanded FDA labeling, as well as the number needed to treat (NNT) to prevent worsening events of heart failure.

The team, led by Scott D. Solomon, MD, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, observed an expanded FDA label is expected to show substantial increase in the potential HF population eligible for sacubitril/valsartan and may prevent up to 180,000 worsening HF events.


In order to estimate the prevalence of HF, self-reported data from the National Health and Nutrition Examination Survey (NHANES) from 2015 - 2018 was used in the study.

Moreover, to determine the eligible cohort for sacubitril/valsartan, investigators excluded patients with a systolic blood pressure (SBP) lower than 100 mm Hg or an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2.

Investigators determined newly eligible patients with HF at higher LVEF ranges based on 4 LVEF cutoffs to define lower than normal: 41% - 50%, which covers HF with mid range ejection fraction; 41% - 55%, in which the upper limit of the confidence interval of treatment effect is entirely confined to the region of benefit in pooled analysis of PARAGON-HF and PARADIGM-HF trials; 41% - 57%, which was the median LVEF value in the PARAGON-HF trial; 41% - 60%, which is the nearest 5-point integer.

The PARAGON-HF trial was a global randomized clinical trial (RCT) that examined sacubitril/valsartan against an active comparator valsartan among adults 50 year and older with symptomatic HFpEF with LVEF of 45% or more.

In order to determine the total burden of HF events, investigators used 3 end points of interest including total HF hospitalizations, total HF hospitalizations and cardiovascular death, and total HF hospitalizations and urgent HF visits and CV death.

Lastly, main outcomes of the study included the number of worsening HF events prevented or postponed if eligible patients were treated with sacubitril/valsartan for 3 years. Data was analyzed from February - June 2021.

Resulting Events

Data on the prevalence of self-reported HF among US adults show an estimate of 5,604,076 (95% CI, 4,674,944 - 6,533,208).

Following the use of exclusion criteria, the study identified a total of 4,682,098 individuals (95% CI, 3,890,581 - 5,473,615) with HF. The analyzed demographics show a mean age of 66.3 years, 42.6% women (n = 1,995,037), and 16.0% (n = 748,045) were Black.

Investigators noted 45.4% of patients with HF (n = 2,124,182) would have previously met LVEF criteria for prior HF with reduced ejection fraction indication.

Further, under the expanded label, eligibility ranged from additional 14% (if LVEF ≤50%) to 39% (if LVEF ≤60%).

As a result, the potential number of adults projected to be newly eligible had a range from 643,161 (95% CI, 534,433 - 751,888; LVEF, 41% - 50%) to 1,838,756 (95% CI, 1,527,911 - 2,149,601; LVEF, 41% - 60%).

Within the PARAGON-HF trial (n = 4796), the 3-year NNT was 20 for total HF hospitalizations, 19 for total HF hospitalizations and CV death, and 17 for total worsening HF events and CV death.

In addition, across all LVEF ranges, the 3-year NNT ranged from 7 - 12 in all 3 end points of interest.

Following this, the implementation of sacubitril/valsartan among newly eligible patients with HF would prevent up to 69,268 worsening HF events (95% CI, 57,558 - 80,978; LVEF, 41% - 50%) to 182,592 worsening HF events (95% CI, 151,725 - 213,460; LVEF, 41% - 60%).


The team concluded the expanded FDA label may increase the HF population eligible for sacubitril/valsartan by up to 1.8 million individuals.

“If prior implementation barriers to sacubitril/valsartan are swiftly overcome, population-level impact on worsening HF events in this high-risk population is certainly possible with a favorable safety/efficacy margin for most individuals,” investigators wrote. “However, challenges based on access, cost, and therapeutic inertia should not be underestimated.”

The study, “Potential Implications of Expanded US Food and Drug Administration Labeling for Sacubitril/Valsartan in the US,” was published online in JAMA Cardiology.

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