@article{34890d11c4524b79aba6829651eb17da,
title = "Biomarker changes as surrogate endpoints in early-phase trials in heart failure with reduced ejection fraction",
abstract = "AIMS: No biomarker has achieved widespread acceptance as a surrogate endpoint for early-phase heart failure (HF) trials. We assessed whether changes over time in a panel of plasma biomarkers were associated with subsequent morbidity/mortality in HF with reduced ejection fraction (HFrEF).METHODS AND RESULTS: In 1040 patients with HFrEF from the BIOSTAT-CHF cohort, we investigated the associations between changes in the plasma concentrations of 30 biomarkers, before (baseline) and after (9 months) attempted optimization of guideline-recommended therapy, on top of the BIOSTAT risk score and the subsequent risk of HF hospitalization/all-cause mortality using Cox regression models. C-statistics were calculated to assess discriminatory power of biomarker changes/month-nine assessment. Changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and WAP four-disulphide core domain protein HE4 (WAP-4C) were the only independent predictors of the outcome after adjusting for their baseline plasma concentration, 28 other biomarkers (both baseline and changes), and BIOSTAT risk score at baseline. When adjusting for month-nine rather than baseline biomarkers concentrations, only changes in NT-proBNP were independently associated with the outcome. The C-statistic of the model including the BIOSTAT risk score and NT-proBNP increased by 4% when changes were considered on top of baseline concentrations and by 1% when changes in NT-proBNP were considered on top of its month-nine concentrations and the BIOSTAT risk score.CONCLUSIONS: Among 30 relevant biomarkers, a change over time was significantly and independently associated with HF hospitalization/all-cause death only for NT-proBNP. Changes over time were modestly more prognostic than baseline or end-values alone. Changes in biomarkers should be further explored as potential surrogate endpoints in early phase HF trials.",
keywords = "Biomarkers, Heart failure with reduced ejection fraction, Phase 2, Randomized trial, Surrogate endpoint, Surrogate outcome",
author = "Gianluigi Savarese and Alicia Uijl and Wouter Ouwerkerk and Jasper Tromp and Anker, {Stefan D} and Kenneth Dickstein and Camilla Hage and Lam, {Carolyn S P} and Lang, {Chim C} and Marco Metra and Ng, {Leong L} and Nicola Orsini and Samani, {Nilesh J} and {van Veldhuisen}, {Dirk J} and Cleland, {John G F} and Voors, {Adriaan A} and Lund, {Lars H}",
note = "Funding Information: BIOSTAT-CHF was funded by a grant from the European Commission (FP7-242209-BIOSTAT-CHF; EudraCT 2010-020808-29). This study has been partially funded by the EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart grant no. 116074. LHL was supported by Karolinska Institutet, the Swedish Research Council [grant 523-2014-2336], the Swedish Heart Lung Foundation [grants 20150557, 20190310], and the Stockholm County Council [grants 20170112, 20190525]. Funding Information: AAV acted as a consultant for Amgen, Bayer AG, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novartis, and received research support from NovoNordisk, Roche Diagnostics. LHL reports consulting fees from Lexicon, Merck, Pharmacosmos, and Myokardia, lecture fees and consulting fees from Vifor, Bayer, Medscape, grant support, lecture fees, and consulting fees AstraZeneca, and Novartis, grant support and consulting fees from Relypsa and Boehringer Ingelheim, grant support from Boston Scientific, and lecture fees from Abbot. Funding Information: BIOSTAT‐CHF was funded by a grant from the European Commission (FP7‐242209‐BIOSTAT‐CHF; EudraCT 2010‐020808‐29). This study has been partially funded by the EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart grant no. 116074. LHL was supported by Karolinska Institutet, the Swedish Research Council [grant 523‐2014‐2336], the Swedish Heart Lung Foundation [grants 20150557, 20190310], and the Stockholm County Council [grants 20170112, 20190525]. Funding Information: GS reports grants and personal fees from Vifor, grants and non‐financial support from Boehringer Ingelheim, personal fees from Societa′ Prodotti Antibiotici, grants from MSD, grants and personal fees from AstraZeneca, personal fees from Roche, personal fees from Servier, grants from Novartis, personal fees from GENESIS, personal fees from Cytokinetics, personal fees from Medtronic, grants from Merck, grants from Bayer outside the submitted work. AU has nothing to disclose. WO has nothing to disclose. JT declares personal fees from Roche diagnostic and US2.ai, outside the submitted work. SDA reports receiving fees from Abbott, Bayer, Boehringer Ingelheim, Cardiac Dimension, Cordio, Impulse Dynamics, Novartis, Occlutech, Servier, and Vifor Pharma, and grant support from Abbott and Vifor Pharma. KD declares no conflict of interest related to the current work. CH reports consulting fees from Novartis and Roche Diagnostics and speaker and honoraria from MSD, supported by the Swedish Research Council [grant 20180899]. CSL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Abbott Diagnostics, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Biofourmis, Boehringer Ingelheim, Boston Scientific, Corvia Medical, Cytokinetics, Darma Inc., Eko.ai Pte Ltd, JanaCare, Janssen Research & Development LLC, Medtronic, Menarini Group, Merck, MyoKardia, Novartis, Novo Nordisk, Radcliffe Group Ltd., Roche Diagnostics, Stealth BioTherapeutics, The Corpus, Vifor Pharma and WebMD Global LLC; and serves as co‐founder & non‐executive director of EKo.ai Pte Ltd. CCL received fees and/or research grants from AstraZeneca, Boehringher Ingelheim, MSD, Menarini Pharma, Novartis, Nono Nordisk, Vifor Pharma, outside the submitted work. Publisher Copyright: {\textcopyright} 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.",
year = "2022",
month = aug,
doi = "10.1002/ehf2.13917",
language = "English",
volume = "9",
pages = "2107--2118",
number = "4",
}