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NT‐proBNP Qualifies as a Surrogate for Clinical End Points in Heart Failure

N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) is a well‐established biomarker in heart failure (HF) but controversially discussed as a potential surrogate marker in HF trials. We analyzed the NT‐proBNP/mortality relationship in real‐world data (RWD) of 108,330 HF patients from the IBM Watson...

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Autores principales: Schmitt, Walter, Rühs, Hauke, Burghaus, Rolf, Diedrich, Christian, Duwal, Sulav, Eissing, Thomas, Garmann, Dirk, Meyer, Michaela, Ploeger, Bart, Lippert, Jörg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360001/
https://www.ncbi.nlm.nih.gov/pubmed/33630302
http://dx.doi.org/10.1002/cpt.2222
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author Schmitt, Walter
Rühs, Hauke
Burghaus, Rolf
Diedrich, Christian
Duwal, Sulav
Eissing, Thomas
Garmann, Dirk
Meyer, Michaela
Ploeger, Bart
Lippert, Jörg
author_facet Schmitt, Walter
Rühs, Hauke
Burghaus, Rolf
Diedrich, Christian
Duwal, Sulav
Eissing, Thomas
Garmann, Dirk
Meyer, Michaela
Ploeger, Bart
Lippert, Jörg
author_sort Schmitt, Walter
collection PubMed
description N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) is a well‐established biomarker in heart failure (HF) but controversially discussed as a potential surrogate marker in HF trials. We analyzed the NT‐proBNP/mortality relationship in real‐world data (RWD) of 108,330 HF patients from the IBM Watson Health Explorys database and compared it with the NT‐proBNP / clinical event end‐point relationship in 20 clinical HF studies. With a hierarchical statistical model, we quantified the functional relationship and interstudy variability. To independently qualify the model, we predicted outcome hazard ratios in five phase III HF studies solely based on NT‐proBNP measured early in the respective study. In RWD and clinical studies, the relationship between NT‐proBNP and clinical outcome is well described by an E(max) model. The NT‐proBNP independent baseline risk (R(0), RWD/studies median (interstudy interquartile range): 5.5%/3.0% (1.7–4.9%)) is very low compared with the potential NT‐proBNP–associated maximum risk (R(max): 55.2%/79.4% (61.5–89.0%)). The NT‐proBNP concentration associated with the half‐maximal risk is comparable in RWD and across clinical studies (EC(50): 3,880/2,414 pg/mL (1,460–4,355 pg/mL)). Model‐based predictions of phase III outcomes, relying on short‐term NT‐proBNP data only, match final trial results with comparable confidence intervals. Our analysis qualifies NT‐proBNP as a surrogate for clinical outcome in HF trials. NT‐proBNP levels after short treatment durations of less than 10 weeks quantitatively predict hazard ratios with confidence levels comparable to final trial readout. Early NT‐proBNP measurement can therefore enable shorter and smaller but still reliable HF trials.
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spelling pubmed-83600012021-08-17 NT‐proBNP Qualifies as a Surrogate for Clinical End Points in Heart Failure Schmitt, Walter Rühs, Hauke Burghaus, Rolf Diedrich, Christian Duwal, Sulav Eissing, Thomas Garmann, Dirk Meyer, Michaela Ploeger, Bart Lippert, Jörg Clin Pharmacol Ther Research N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) is a well‐established biomarker in heart failure (HF) but controversially discussed as a potential surrogate marker in HF trials. We analyzed the NT‐proBNP/mortality relationship in real‐world data (RWD) of 108,330 HF patients from the IBM Watson Health Explorys database and compared it with the NT‐proBNP / clinical event end‐point relationship in 20 clinical HF studies. With a hierarchical statistical model, we quantified the functional relationship and interstudy variability. To independently qualify the model, we predicted outcome hazard ratios in five phase III HF studies solely based on NT‐proBNP measured early in the respective study. In RWD and clinical studies, the relationship between NT‐proBNP and clinical outcome is well described by an E(max) model. The NT‐proBNP independent baseline risk (R(0), RWD/studies median (interstudy interquartile range): 5.5%/3.0% (1.7–4.9%)) is very low compared with the potential NT‐proBNP–associated maximum risk (R(max): 55.2%/79.4% (61.5–89.0%)). The NT‐proBNP concentration associated with the half‐maximal risk is comparable in RWD and across clinical studies (EC(50): 3,880/2,414 pg/mL (1,460–4,355 pg/mL)). Model‐based predictions of phase III outcomes, relying on short‐term NT‐proBNP data only, match final trial results with comparable confidence intervals. Our analysis qualifies NT‐proBNP as a surrogate for clinical outcome in HF trials. NT‐proBNP levels after short treatment durations of less than 10 weeks quantitatively predict hazard ratios with confidence levels comparable to final trial readout. Early NT‐proBNP measurement can therefore enable shorter and smaller but still reliable HF trials. John Wiley and Sons Inc. 2021-03-27 2021-08 /pmc/articles/PMC8360001/ /pubmed/33630302 http://dx.doi.org/10.1002/cpt.2222 Text en © 2021 Bayer AG. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Schmitt, Walter
Rühs, Hauke
Burghaus, Rolf
Diedrich, Christian
Duwal, Sulav
Eissing, Thomas
Garmann, Dirk
Meyer, Michaela
Ploeger, Bart
Lippert, Jörg
NT‐proBNP Qualifies as a Surrogate for Clinical End Points in Heart Failure
title NT‐proBNP Qualifies as a Surrogate for Clinical End Points in Heart Failure
title_full NT‐proBNP Qualifies as a Surrogate for Clinical End Points in Heart Failure
title_fullStr NT‐proBNP Qualifies as a Surrogate for Clinical End Points in Heart Failure
title_full_unstemmed NT‐proBNP Qualifies as a Surrogate for Clinical End Points in Heart Failure
title_short NT‐proBNP Qualifies as a Surrogate for Clinical End Points in Heart Failure
title_sort nt‐probnp qualifies as a surrogate for clinical end points in heart failure
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360001/
https://www.ncbi.nlm.nih.gov/pubmed/33630302
http://dx.doi.org/10.1002/cpt.2222
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