@article{e797a5618cf8466cae11aa1e58e1e1d8,
title = "Increase in BNP in Response to Endothelin-Receptor Antagonist Atrasentan Is Associated With Incident Heart Failure",
abstract = "Background: The endothelin receptor antagonist atrasentan reduced the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease (CKD) in the SONAR (Study of Diabetic Nephropathy with Atrasentan) trial, although with a numerically higher incidence of heart failure (HF) hospitalization. Objectives: The purpose of this study was to assess if early changes in B-type natriuretic peptide (BNP) and body weight during atrasentan treatment predict HF risk. Methods: Participants with type 2 diabetes and CKD entered an open-label enrichment phase to assess response to atrasentan 0.75 mg/day. Participants without substantial fluid retention (>3 kg body weight increase or BNP increase to >300 pg/mL), were randomized to atrasentan 0.75 mg/day or placebo. Cox proportional hazards regression was used to assess the effects of atrasentan vs placebo on the prespecified safety outcome of HF hospitalizations. Results: Among 3,668 patients, 73 (4.0%) participants in the atrasentan and 51 (2.8%) in the placebo group developed HF (HR: 1.39; 95% CI: 0.97-1.99; P = 0.072). In a multivariable analysis, HF risk was associated with higher baseline BNP (HR: 2.32; 95% CI: 1.81-2.97) and percent increase in BNP during response enrichment (HR: 1.46; 95% CI: 1.08-1.98). Body weight change was not associated with HF. Exclusion of patients with at least 25% BNP increase during enrichment attenuated the risk of HF with atrasentan (HR: 1.02; 95% CI: 0.66-1.56) while retaining nephroprotective effects (HR: 0.58; 95% CI: 0.44-0.78). Conclusions: In patients with type 2 diabetes and CKD, baseline BNP and early changes in BNP in response to atrasentan were associated with HF hospitalization, highlighting the importance of natriuretic peptide monitoring upon initiation of atrasentan treatment.",
keywords = "atrasentan, chronic kidney disease, endothelin receptor antagonist, heart failure, type 2 diabetes mellitus",
author = "Smeijer, {J. David} and Jeroen Koomen and Kohan, {Donald E.} and McMurray, {John J.V.} and Bakris, {George L.} and Ricardo Correa-Rotter and Hou, {Fan Fan} and Januzzi, {James L.} and Kitzman, {Dalane W.} and Kolansky, {Daniel M.} and Hirofumi Makino and Vlado Perkovic and Sheldon Tobe and Parving, {Hans Henrik} and {de Zeeuw}, Dick and Heerspink, {Hiddo J.L.}",
note = "Funding Information: This study was conducted in the framework of the IMI BEAt-DKD program. The BEAt-DKD project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115974. This Joint Undertaking receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation program and EFPIA. Dr Kohan has served as a consultant for AbbVie, AstraZeneca, Chinook Therapeutics, and Travere Therapeutics. Dr Bakris has received support from T32 National Institutes of Health grant DK07011; has served as a consultant to Merck, Bayer, KBP Biosciences, Ionis, Alnylam, AstraZeneca, Quantum Genomics, Horizon, and Novo Nordisk; and has served on the steering committee of trials for Bayer, Quantum Genomics, Alnylam, and Novo Nordisk. Dr Correa-Rotter has served on advisory boards for Boehringer and AstraZeneca; and has been a speaker for AstraZeneca, Boehringer Ingelheim, AbbVie, Takeda, Amgen, and Janssen. Dr Hou has served as a consultant for and received honoraria from AbbVie and AstraZeneca. Dr Januzzi is supported by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife and Novartis; has received consulting income from Abbott Diagnostics, Boehringer Ingelheim, Janssen, Novartis, and Roche Diagnostics; and has participated in clinical endpoint committees/data safety monitoring boards for AbbVie, Siemens, Takeda, and Vifor. Dr Kitzman has received grant funding from Novartis, Bayer, NovoNordisk, and AstraZeneca; honoraria for consulting from AbbVie, Bayer, Merck, Medtronic, Relypsa, Merck, Corvia Medical, Boehringer Ingelheim, NovoNordisk, AstraZeneca, Keyto, Pfizer, and Novartis; stock ownership in Gilead Sciences. Dr Kolansky has participated in clinical endpoint committees for ACI Clinical, George Clinical, and the Baim Institute for Clinical Research. Dr Makino has served on steering committees for AbbVie and Teijin; and has served on advisory boards for Boehringer Ingelheim and Travere Therapeutics. Dr Perkovic has served on steering committees for trials funded by AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Novo Nordisk, Retrophin, and Tricida; and has participated in scientific presentations or advisory boards with AbbVie, Astellas, AstraZeneca, Bayer, Baxter, Bristol Myers Squibb, Boehringer Ingelheim, Dimerix, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Mitsubishi Tanabe, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Sanofi, Servier, and Tricida. Dr Tobe has participated on a steering committee for Bayer Fidelio/Figaro studies; and has served on the Speakers Bureau of Servier and Pfizer. Dr Parving was the co-chair of the SONAR study steering committee; and has served as a consultant for AbbVie. Dr de Zeeuw has served on advisory boards and/or as a speaker for Bayer, Boehringer Ingelheim, Fresenius, Mitsubishi-Tanabe, and Travere Pharmaceuticals; has served on Steering Committees and/or as a speaker for AbbVie and Janssen; and has served on the Data Safety and Monitoring Committees for Bayer, with honoraria paid to the institution and consultant/speaker. Dr Heerspink is supported by a VIDI (917.15.306) grant from the Netherlands Organisation for Scientific Research; has served as a consultant for AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Fresenius, Gilead, Janssen, Merck, Mundipharma, Mitsubishi Tanabe, and Retrophin; and has received grant support from AbbVie, AstraZeneca, Boehringer Ingelheim, and Janssen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = jul,
doi = "10.1016/j.jchf.2022.03.004",
language = "English",
volume = "10",
pages = "498--507",
journal = "JACC: Heart Failure",
issn = "2213-1779",
publisher = "Elsevier BV",
number = "7",
}
