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). Met...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-08-01
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| Series: | ESC Heart Failure |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ehf2.13917 |
| _version_ | 1818197077035843584 |
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| author | Gianluigi Savarese Alicia Uijl Wouter Ouwerkerk Jasper Tromp Stefan D. Anker Kenneth Dickstein Camilla Hage Carolyn S.P. Lam Chim C. Lang Marco Metra Leong L. Ng Nicola Orsini Nilesh J. Samani Dirk J. vanVeldhuisen John G.F. Cleland Adriaan A. Voors Lars H. Lund |
| author_facet | Gianluigi Savarese Alicia Uijl Wouter Ouwerkerk Jasper Tromp Stefan D. Anker Kenneth Dickstein Camilla Hage Carolyn S.P. Lam Chim C. Lang Marco Metra Leong L. Ng Nicola Orsini Nilesh J. Samani Dirk J. vanVeldhuisen John G.F. Cleland Adriaan A. Voors Lars H. Lund |
| author_sort | Gianluigi Savarese |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T01:44:14Z |
| format | Article |
| id | doaj.art-2a10c1e7c4934e62b1a56f214be0a7f7 |
| institution | Directory Open Access Journal |
| issn | 2055-5822 |
| language | English |
| last_indexed | 2024-12-12T01:44:14Z |
| publishDate | 2022-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | ESC Heart Failure |
| spelling | doaj.art-2a10c1e7c4934e62b1a56f214be0a7f72022-12-22T00:42:37ZengWileyESC Heart Failure2055-58222022-08-01942107211810.1002/ehf2.13917Biomarker changes as surrogate endpoints in early‐phase trials in heart failure with reduced ejection fractionGianluigi Savarese0Alicia Uijl1Wouter Ouwerkerk2Jasper Tromp3Stefan D. Anker4Kenneth Dickstein5Camilla Hage6Carolyn S.P. Lam7Chim C. Lang8Marco Metra9Leong L. Ng10Nicola Orsini11Nilesh J. Samani12Dirk J. vanVeldhuisen13John G.F. Cleland14Adriaan A. Voors15Lars H. Lund16Division of Cardiology, Department of Medicine Karolinska Institutet Stockholm SwedenDivision of Cardiology, Department of Medicine Karolinska Institutet Stockholm SwedenNational Heart Centre Singapore SingaporeNational Heart Centre Singapore SingaporeDepartment of Cardiology (CVK); and Berlin Institute of Health Center for Regenerative Therapies (BCRT); German Centre for Cardiovascular Research (DZHK) partner site Berlin Charité Universitätsmedizin Berlin Berlin GermanyStavanger University Hospital Stavanger NorwayDivision of Cardiology, Department of Medicine Karolinska Institutet Stockholm SwedenNational Heart Centre Singapore SingaporeDivision of Molecular and Clinical Medicine University of Dundee Dundee UKCardiology Unit, ASST Spedali Civili and Department of Medical and Surgical Specialties, Radiological Sciences and Public Health University of Brescia Brescia ItalyDepartment of Cardiovascular Sciences University of Leicester, Glenfield Hospital, and NIHR Leicester Biomedical Research Centre Leicester UKDepartment of Global Public Health Karolinska Institutet Stockholm SwedenDepartment of Cardiovascular Sciences University of Leicester, Glenfield Hospital, and NIHR Leicester Biomedical Research Centre Leicester UKDepartment of Cardiology, University Medical Center Groningen University of Groningen Groningen The NetherlandsRobertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow and National Heart & Lung Institute Imperial College London UKDepartment of Cardiology, University Medical Center Groningen University of Groningen Groningen The NetherlandsDivision of Cardiology, Department of Medicine Karolinska Institutet Stockholm SwedenAbstract 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.https://doi.org/10.1002/ehf2.13917BiomarkersSurrogate endpointSurrogate outcomeHeart failure with reduced ejection fractionPhase 2Randomized trial |
| spellingShingle | Gianluigi Savarese Alicia Uijl Wouter Ouwerkerk Jasper Tromp Stefan D. Anker Kenneth Dickstein Camilla Hage Carolyn S.P. Lam Chim C. Lang Marco Metra Leong L. Ng Nicola Orsini Nilesh J. Samani Dirk J. vanVeldhuisen John G.F. Cleland Adriaan A. Voors Lars H. Lund Biomarker changes as surrogate endpoints in early‐phase trials in heart failure with reduced ejection fraction ESC Heart Failure Biomarkers Surrogate endpoint Surrogate outcome Heart failure with reduced ejection fraction Phase 2 Randomized trial |
| title | Biomarker changes as surrogate endpoints in early‐phase trials in heart failure with reduced ejection fraction |
| title_full | Biomarker changes as surrogate endpoints in early‐phase trials in heart failure with reduced ejection fraction |
| title_fullStr | Biomarker changes as surrogate endpoints in early‐phase trials in heart failure with reduced ejection fraction |
| title_full_unstemmed | Biomarker changes as surrogate endpoints in early‐phase trials in heart failure with reduced ejection fraction |
| title_short | Biomarker changes as surrogate endpoints in early‐phase trials in heart failure with reduced ejection fraction |
| title_sort | biomarker changes as surrogate endpoints in early phase trials in heart failure with reduced ejection fraction |
| topic | Biomarkers Surrogate endpoint Surrogate outcome Heart failure with reduced ejection fraction Phase 2 Randomized trial |
| url | https://doi.org/10.1002/ehf2.13917 |
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