Natriuretic Peptides, Kidney Function, and Clinical Outcomes in Heart Failure With Preserved Ejection Fraction

Brendon L Neuen; Muthiah Vaduganathan; Brian L Claggett; Iris Beldhuis; Peder Myhre; Akshay S Desai; Hicham Skali; Finnian R Mc Causland; Martina McGrath; Inder Anand; Michael R Zile; Marc A Pfeffer; John J V McMurray; Scott D Solomon

doi:10.1016/j.jchf.2024.08.009

Natriuretic Peptides, Kidney Function, and Clinical Outcomes in Heart Failure With Preserved Ejection Fraction

JACC Heart Fail. 2024 Aug 31:S2213-1779(24)00610-3. doi: 10.1016/j.jchf.2024.08.009. Online ahead of print.

Authors

Affiliations

¹ Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; The George Institute for Global Health, University of New South Wales, Sydney, Australia; Department of Renal Medicine, Royal North Shore Hospital, Sydney, Australia.
² Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Division of Cardiovascular Medicine, Center for Cardiometabolic Implementation Science, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
³ Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁴ Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Cardiology, University of Groningen, University of Medical Center Groningen, Groningen, the Netherlands.
⁵ Division of Medicine, Department of Cardiology, Akershus University Hospital, Lørenskog, Norway.
⁶ Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁷ VA Medical Center and University of Minnesota, Minneapolis, Minnesota, USA.
⁸ Division of Cardiology, Medical University of South Carolina, Ralph H. Johnson Department of Veterans Affairs Health Care System, Charleston, South Carolina, USA.
⁹ British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
¹⁰ Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. Electronic address: sdsolomon@bwh.harvard.edu.

PMID: 39365237
DOI: 10.1016/j.jchf.2024.08.009

Abstract

Background: N-terminal pro-B-type natriuretic peptides (NT-proBNPs) are guideline-recommended biomarkers for risk stratification in patients with heart failure. However, NT-proBNP levels are often elevated in chronic kidney disease, introducing uncertainty about their prognostic relevance in persons across a broad range of estimated glomerular filtration rate (eGFR).

Objectives: The aim of this study was to assess the association of NT-proBNP with cardiovascular and mortality outcomes in patients with heart failure and mildly reduced or preserved ejection fraction, stratified by baseline kidney function.

Methods: A pooled analysis was conducted of participants with NT-proBNP and eGFR measured at baseline in the I-PRESERVE (Irbesartan in Heart Failure and Preserved Ejection Fraction), TOPCAT (Americas region) (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function), PARAGON (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction), and DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trials. The relationship between NT-proBNP and eGFR was assessed using piecewise linear regression. Using multivariable Cox and Poisson regression models, the association of NT-proBNP with outcomes across a range of eGFR was evaluated. The primary outcome was hospitalization for heart failure or cardiovascular death.

Results: Among 14,831 participants (mean age: 72.1 years; 50.3% female; mean eGFR: 63.3 mL/min/1.73 m², and median NT-proBNP: 840 pg/mL) followed up for a median 33.5 months, there were 3,092 primary outcomes. NT-proBNP levels increased by 9%, 8%, and 23% per 10 mL/min/1.73 m² lower eGFR in patients with baseline eGFR ≥60, 45-<60, and <45 mL/min/1.73 m², respectively (P for nonlinearity < 0.001). Each doubling in NT-proBNP was associated with a 37% relative increase in the primary outcome (HR: 1.37; 95% CI: 1.34-1.41), consistent across different eGFR categories (P for interaction = 0.42). For the same incidence of the primary outcome, NT-proBNP levels were approximately 2.5- to 3.5-fold lower in patients with eGFR <45 mL/min/1.73 m², compared with patients with eGFR ≥60 mL/min/1.73 m². Similar patterns were observed across all outcomes studied, including cardiovascular and noncardiovascular death.

Conclusions: The same NT-proBNP concentration predicts a substantially higher absolute risk of adverse outcomes for people with heart failure and reduced kidney function, compared with those with preserved kidney function. These data call into question proposals for higher NT-proBNP references ranges in people with CKD, and suggest that reduced kidney function per se should not be a reason to disregard higher NT-proBNP levels.

Keywords: N-terminal pro–B-type natriuretic peptide; chronic renal insufficiency; glomerular filtration rate; heart failure; kidney; natriuretic peptides; treatment outcome.