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

Journal: JACC. Heart failure 2022;10(7):498-507

PMID: 35772861

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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).

Address: Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands.; Division of Nephrology, University of Utah Health, Salt Lake City, Utah, USA.; British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.; American Society of Hypertension Comprehensive Hypertension Center, University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.; National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico.; Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, Guangzhou, China.; Cardiology Division, Massachusetts General Hospital, Harvard Medical School and Baim Institute for Clinical Research, Boston, Massachusetts, USA.; Sections on Cardiovascular Disease and Geriatrics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.; Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Okayama University, Okayama, Japan.; George Institute for Global Health, Newtown, Australia; University of New South Wales, Sydney, New South Wales, Australia.; Division of Nephrology, Sunnybrook Health Sciences Centre, University of Toronto and the Northern Ontario School of Medicine, Toronto, Ontario, Canada.; Department of Medical Endocrinology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark.; Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands; George Institute for Global Health, Newtown, Australia. Electronic address: [email protected].

DOI: 10.1016/j.jchf.2022.03.004