Natriuretic Peptides as Inclusion Criteria in Clinical Trials: A JACC: Heart Failure Position Paper

doi:10.1016/j.jchf.2019.12.010

JACC: Heart Failure

Volume 8, Issue 5, May 2020, Pages 347-358

https://doi.org/10.1016/j.jchf.2019.12.010 Get rights and content

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Highlights

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BNP and NT-proBNP are used as inclusion criteria in several HF clinical trials.
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Despite widespread use, there is inconsistency in how BNP and NT-proBNP are utilized.
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We call for standardization of natriuretic peptide inclusion criteria across HF trials.

Abstract

This study investigated the use of natriuretic peptides as inclusion criteria and to develop recommendations regarding their use. B-type natriuretic peptide (BNP) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) are commonly used as inclusion criteria for heart failure (HF) clinical trials, but no consensus exists regarding their optimal use for this purpose. A comprehensive search of the Aggregate Analysis of ClincalTrials.gov database identified 3,446 HF trials. Of these, 365 recently completed or ongoing HF clinical trials (10.6%) used either BNP or NT-proBNP as inclusion criteria. A panel of experts discussed current practices and a path forward for the use of natriuretic peptides as inclusion criteria for HF trials. Significant variations existed across trials regarding which natriuretic peptide and which cutoff value were used. Overall, 43% used both natriuretic peptides, 33% used only NT-proBNP, and 24% used only BNP in determining eligibility. Studies using BNP and NT-proBNP concentrations as inclusion criteria had higher cardiovascular event rates and higher concentrations for study entry and were generally associated with higher event rates. Areas of uncertainty included use in certain patient populations in which natriuretic peptides are historically lower (e.g., black patients, obese patients, patients with HF with preserved ejection fraction) or higher (older patients, patients with atrial fibrillation). This paper discusses best practices regarding use of BNP or NT-proBNP in clinical trials and identification of gaps in medical literature, including importance of documentation in ClinicalTrials.gov studies to inform future research efforts.

Central Illustration

Key Words

biomarkers

clinical trials

inclusion criteria

natriuretic peptides

Abbreviations and Acronyms

atrial fibrillation

BMI

body mass index

BNP

B-type natriuretic peptide

CAD

coronary artery disease

CKD

chronic kidney disease

eGFR

estimated glomerular filtration rate

heart failure

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

NT-proBNP

N-terminal pro–B-type natriuretic peptide

RRT

renal replacement therapy

Cited by (0)

: Dr. Ibrahim is supported by the Dennis and Marilyn Barry Research Fund in Cardiology (Boston, Massachusetts). Dr. Januzzi is supported by the Hutter Family Professorship (Boston, Massachusetts). Dr. Ibrahim has received honorarium from Roche Diagnostics. Dr. Burnett is a consultant for Novartis. Dr. Felker has received research support from U.S. National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), American Heart Association, Amgen, Merck, Cytokinetics, and Roche Diagnostics; and is a consultant for Novartis, Amgen, Bristol-Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Relypsa, V-Wave, MyoKardia, Innolife, EBR Systems, Arena, Abbott, Sphingotec, Roche Diagnostics, Alnylam, LivaNova, Rocket Pharma, and SC Pharma. Dr. O’Connor has received support from NIH/NHLBI, U.S. Food and Drug Administration, Merck, Bayer, Abbott, and Medtronic; and is a consultant for Merck, Bayer, and Bristol-Myers Squibb. Dr. Fiuzat has received research funding from Roche Diagnostics. Dr. O’Connor has received research funding from Roche Diagnostics; and is a consultant for Merck, Bayer, Bristol-Myers Squibb, Windtree, and Arena Pharmaceuticals. Dr. Solomon has received research support from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur, Theracos; and is a consultant for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya. Dr. Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/National Center for Advancing Translational Sciences award UL 1TR002541); and serves on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, and Boehringer Ingelheim. Dr. Zile has received research support from NHLBI, Department of Defense, and Veterans Administration; and is a consultant for Abbott, Boston Scientific, CVRx, EBR Systems, Endotronics, Edwards Lifesciences, Ironwood, Merck, Medtronic, MyoKardia, Novartis, and V Wave. Dr. Januzzi is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received support from Novartis Pharmaceuticals, Roche Diagnostics, Abbott, Singulex, and Prevencio; is a consultant for Abbott, Janssen, Novartis, Pfizer, Merck, and Roche Diagnostics; and serves on clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Boehringer Ingelheim, Janssen, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Barry Greenberg, MD, served as Guest Editor for this paper.

: The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Heart Failure author instructions page.