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Heart Failure Population with Therapeutic Response to Sacubitril/Valsartan, Spironolactone and Candesartan: FDA Perspective

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Abstract

Sacubitril/valsartan was approved by the Food and Drug Administration in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure (HHF) in patients with chronic heart failure with reduced ejection fraction defined as left ventricular ejection fraction (LVEF) ≤ 40%. This approval was based on PARADIGM-HF trial. Subsequently, PARAGON-HF was conducted to support a claim for sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF), defined as LVEF ≥ 45%. PARAGON-HF failed to meet the pre-defined threshold for statistical significance for the primary composite endpoint. However, analysis of the primary endpoint by LVEF as a continuous variable demonstrated that sacubitril/valsartan was efficacious in patients with mildly abnormal LVEF similar to patients with LVEF ≤ 40% evaluated in PARADIGM-HF. This led to a broader indication for sacubitril/valsartan—“to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. LVEF is a variable measure, so use clinical judgment in deciding whom to treat.” This article describes the rationale for a revised indication for sacubitril/valsartan, emphasizes the need to go beyond a dichotomous classification of HF based on a traditional LVEF cut-off and clarifies that the product label for sacubitril/valsartan does not refer to HFpEF.

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Authors and Affiliations

  1. Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

    Charu Gandotra, Fortunato F. Senatore & Norman L. Stockbridge

  2. Office of Biostatistics, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

    Jennifer Clark, Ququan Liu & Jialu Zhang

  3. Rose Regulatory Consulting, LLC, Bethesda, MD, USA

    Martin Rose

Authors
  1. Charu Gandotra
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  2. Jennifer Clark
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  3. Ququan Liu
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  4. Fortunato F. Senatore
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  5. Martin Rose
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  6. Jialu Zhang
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  7. Norman L. Stockbridge
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Correspondence to Charu Gandotra.

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Gandotra, C., Clark, J., Liu, Q. et al. Heart Failure Population with Therapeutic Response to Sacubitril/Valsartan, Spironolactone and Candesartan: FDA Perspective. Ther Innov Regul Sci 56, 4–7 (2022). https://doi.org/10.1007/s43441-021-00347-z

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  • DOI: https://doi.org/10.1007/s43441-021-00347-z

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