Increase in BNP in Response to Endothelin-Receptor Antagonist Atrasentan Is Associated With Incident Heart Failure

J David Smeijer; Jeroen Koomen; Donald E Kohan; John J V McMurray; George L Bakris; Ricardo Correa-Rotter; Fan-Fan Hou; James L Januzzi; Dalane W Kitzman; Daniel M Kolansky; Hirofumi Makino; Vlado Perkovic; Sheldon Tobe; Hans-Henrik Parving; Dick de Zeeuw; Hiddo J L Heerspink

doi:10.1016/j.jchf.2022.03.004

Increase in BNP in Response to Endothelin-Receptor Antagonist Atrasentan Is Associated With Incident Heart Failure

J David Smeijer, Jeroen Koomen, Donald E Kohan, John J V McMurray, George L Bakris, Ricardo Correa-Rotter, Fan-Fan Hou, James L Januzzi, Dalane W Kitzman, Daniel M Kolansky, Hirofumi Makino, Vlado Perkovic, Sheldon Tobe, Hans-Henrik Parving, Dick de Zeeuw, Hiddo J L Heerspink^*

^*Corresponding author for this work

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. (Study Of Diabetic Nephropathy With Atrasentan [SONAR]; NCT01858532).

Original language	English
Journal	JACC. Heart failure
Volume	10
Issue number	7
Pages (from-to)	498-507
Number of pages	10
ISSN	2213-1779
DOIs	https://doi.org/10.1016/j.jchf.2022.03.004
Publication status	Published - Jul 2022

Keywords

Atrasentan/therapeutic use
Diabetes Mellitus, Type 2/complications
Diabetic Nephropathies/complications
Double-Blind Method
Endothelin Receptor Antagonists/therapeutic use
Endothelins/therapeutic use
Heart Failure/complications
Humans
Natriuretic Peptide, Brain/therapeutic use
Renal Insufficiency, Chronic/complications
Weight Gain

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Smeijer, J. D., Koomen, J., Kohan, D. E., McMurray, J. J. V., Bakris, G. L., Correa-Rotter, R., Hou, F.-F., Januzzi, J. L., Kitzman, D. W., Kolansky, D. M., Makino, H., Perkovic, V., Tobe, S., Parving, H.-H., de Zeeuw, D., & Heerspink, H. J. L. (2022). Increase in BNP in Response to Endothelin-Receptor Antagonist Atrasentan Is Associated With Incident Heart Failure. JACC. Heart failure, 10(7), 498-507. https://doi.org/10.1016/j.jchf.2022.03.004

Smeijer, JD, Koomen, J, Kohan, DE, McMurray, JJV, Bakris, GL, Correa-Rotter, R, Hou, F-F, Januzzi, JL, Kitzman, DW, Kolansky, DM, Makino, H, Perkovic, V, Tobe, S, Parving, H-H, de Zeeuw, D & Heerspink, HJL 2022, 'Increase in BNP in Response to Endothelin-Receptor Antagonist Atrasentan Is Associated With Incident Heart Failure', JACC. Heart failure, vol. 10, no. 7, pp. 498-507. https://doi.org/10.1016/j.jchf.2022.03.004

@article{6a5ef6361b304e6e817098e51aaa78ba,

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. (Study Of Diabetic Nephropathy With Atrasentan [SONAR]; NCT01858532).",

keywords = "Atrasentan/therapeutic use, Diabetes Mellitus, Type 2/complications, Diabetic Nephropathies/complications, Double-Blind Method, Endothelin Receptor Antagonists/therapeutic use, Endothelins/therapeutic use, Heart Failure/complications, Humans, Natriuretic Peptide, Brain/therapeutic use, Renal Insufficiency, Chronic/complications, Weight Gain",

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 Fan-Fan Hou and Januzzi, {James L} and Kitzman, {Dalane W} and Kolansky, {Daniel M} and Hirofumi Makino and Vlado Perkovic and Sheldon Tobe and Hans-Henrik Parving and {de Zeeuw}, Dick and Heerspink, {Hiddo J L}",

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",

}

TY - JOUR

T1 - Increase in BNP in Response to Endothelin-Receptor Antagonist Atrasentan Is Associated With Incident Heart Failure

AU - Smeijer, J David

AU - Koomen, Jeroen

AU - Kohan, Donald E

AU - McMurray, John J V

AU - Bakris, George L

AU - Correa-Rotter, Ricardo

AU - Hou, Fan-Fan

AU - Januzzi, James L

AU - Kitzman, Dalane W

AU - Kolansky, Daniel M

AU - Makino, Hirofumi

AU - Perkovic, Vlado

AU - Tobe, Sheldon

AU - Parving, Hans-Henrik

AU - de Zeeuw, Dick

AU - Heerspink, Hiddo J L

PY - 2022/7

Y1 - 2022/7

N2 - 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. (Study Of Diabetic Nephropathy With Atrasentan [SONAR]; NCT01858532).

AB - 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. (Study Of Diabetic Nephropathy With Atrasentan [SONAR]; NCT01858532).

KW - Atrasentan/therapeutic use

KW - Diabetes Mellitus, Type 2/complications

KW - Diabetic Nephropathies/complications

KW - Double-Blind Method

KW - Endothelin Receptor Antagonists/therapeutic use

KW - Endothelins/therapeutic use

KW - Heart Failure/complications

KW - Humans

KW - Natriuretic Peptide, Brain/therapeutic use

KW - Renal Insufficiency, Chronic/complications

KW - Weight Gain

UR - http://www.scopus.com/inward/record.url?scp=85132771235&partnerID=8YFLogxK

U2 - 10.1016/j.jchf.2022.03.004

DO - 10.1016/j.jchf.2022.03.004

M3 - Journal article

C2 - 35772861

SN - 2213-1779

VL - 10

SP - 498

EP - 507

JO - JACC. Heart failure

JF - JACC. Heart failure

IS - 7

ER -

Increase in BNP in Response to Endothelin-Receptor Antagonist Atrasentan Is Associated With Incident Heart Failure

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