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Original Investigation
September 15, 2021

Potential Implications of Expanded US Food and Drug Administration Labeling for Sacubitril/Valsartan in the US

Author Affiliations
  • 1Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 2Duke Clinical Research Institute and Division of Cardiology, Duke University School of Medicine, Durham, North Carolina
  • 3Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
  • 4British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland
  • 5Ahmanson-UCLA Cardiomyopathy Center, University of California, Los Angeles
  • 6Associate Editor for Health Care Quality and Guidelines, JAMA Cardiology
JAMA Cardiol. Published online September 15, 2021. doi:10.1001/jamacardio.2021.3651
Key Points

Question  What are the implications of expanded US Food and Drug Administration (FDA) labeling for sacubitril/valsartan for use in individuals with chronic heart failure (HF) with left ventricular ejection fraction (LVEF) lower than normal in the US?

Findings  In this decision analytical model study including an estimated 4 682 098 adults, the number of adults projected to potentially be newly eligible varied by the definition of FDA labeling of lower than normal LVEF from 643 161 (LVEF of 41% to 50%) to 1 838 756 (LVEF of 41% to 60%). Comprehensive implementation of sacubitril/valsartan among newly eligible patients was empirically estimated to prevent up to 69 268 worsening HF events (LVEF of 41% to 50%) to 182 592 worsening HF events (LVEF of 41% to 60%) over 3 years of treatment.

Meaning  The expanded FDA labeling is positioned to substantially increase the potential HF population eligible for sacubitril/valsartan by up to 1.8 million individuals and has the potential to prevent or postpone as many as 180 000 worsening HF events, depending on the definition of normal LVEF.

Abstract

Importance  The US Food and Drug Administration (FDA) expanded labeling for sacubitril/valsartan for use in individuals with chronic heart failure (HF) with left ventricular ejection fraction (LVEF) lower than normal. The population-level implications of implementation of sacubitril/valsartan at higher LVEF ranges is unknown. While the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial did not meet its primary end point, the trial may provide useful information in projecting expected clinical events among treated individuals.

Objective  To quantify newly eligible treatment candidates for sacubitril/valsartan under the expanded FDA labeling and to apply treatment effects and the number needed to treat (NNT) to prevent 1 worsening HF event derived from subgroups of the PARAGON-HF trial who fall under the revised FDA label.

Design, Setting, and Participants  Newly eligible treatment candidates were estimated by mapping the LVEF distribution from 559 520 adult patients hospitalized between 2014 and 2019 in the Get With The Guidelines–Heart Failure registry to adults self-identifying with HF in the National Health and Nutrition Examination Survey (2015 to 2018). The NNT with 3 years of treatment for 3 end points of interest (total HF hospitalizations, total HF hospitalizations and cardiovascular death, and total HF hospitalizations and urgent HF visits and cardiovascular death) were estimated from the PARAGON-HF trial. Data were analyzed from February to June 2021.

Main Outcomes and Measures  Number of worsening HF events prevented or postponed if eligible patients were treated with sacubitril/valsartan for 3 years.

Results  Of an estimated 4 682 098 adults, the mean (SE) age was 66.3 (0.8) years, 1 995 037 (42.6%) were women, and 748 045 (16.0%) were Black. The potential number of adults projected to be newly eligible varied by the definition of FDA labeling of lower than normal LVEF from 643 161 (95% CI, 534 433-751 888; LVEF of 41% to 50%) to 1 838 756 (95% CI, 1 527 911-2 149 601; LVEF of 41% to 60%). In the PARAGON-HF trial, the NNT to prevent a worsening HF event (range, 7 to 12 patients) was consistent irrespective of specific LVEF range selected. Comprehensive implementation of sacubitril/valsartan among newly eligible patients was empirically estimated to prevent up to 69 268 (95% CI, 57 558-80 978) worsening HF events (LVEF of 41% to 50%) to 182 592 (95% CI, 151 725-213 460) worsening HF events (LVEF of 41% to 60%).

Conclusions and Relevance  The expanded FDA labeling is positioned to substantially increase the potential HF population eligible for sacubitril/valsartan by up to 1.8 million individuals and has the potential to prevent or postpone as many as 180 000 worsening HF events, depending on the definition of normal LVEF.

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