Endothelin-1, outcomes in patients with heart failure and reduced ejection fraction, and effects of dapagliflozin: Findings from DAPA-HF

Yeoh, S. E. et al. (2023) Endothelin-1, outcomes in patients with heart failure and reduced ejection fraction, and effects of dapagliflozin: Findings from DAPA-HF. Circulation, (doi: 10.1161/CIRCULATIONAHA.122.063327) (PMID:37039015) (Early Online Publication)

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BACKGROUND: ET-1 (endothelin-1) is implicated in the pathophysiology of heart failure and renal disease. Its prognostic importance and relationship with kidney function in patients with heart failure with reduced ejection fraction receiving contemporary treatment are uncertain. We investigated these and the efficacy of dapagliflozin according to ET-1 level in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure). METHODS: We investigated the incidence of the primary outcome (cardiovascular death or worsening heart failure), change in kidney function, and the effect of dapagliflozin according to baseline ET-1 concentration, adjusting in Cox models for other recognized prognostic variables in heart failure including NT-proBNP (N-terminal pro-B-type natriuretic peptide). We also examined the effect of dapagliflozin on ET-1 level. RESULTS: Overall, 3048 participants had baseline ET-1 measurements of: tertile 1 (T1; ≤3.28 pg/mL; n=1016); T2 (>3.28–4.41 pg/mL; n=1022); and T3 (>4.41 pg/mL; n=1010). Patients with higher ET-1 were more likely male, more likely obese, and had lower left ventricular ejection fraction, lower estimated glomerular filtration rate, worse functional status, and higher NT-proBNP and hs-TnT (high-sensitivity troponin-T). In the adjusted Cox models, higher baseline ET-1 was independently associated with worse outcomes and steeper decline in kidney function (adjusted hazard ratio for primary outcome of 1.95 [95% CI, 1.53–2.50] for T3 and 1.36 [95% CI, 1.06–1.75] for T2; both versus T1; estimated glomerular filtration rate slope: T3, –3.19 [95% CI, –3.66 to –2.72] mL/min/1.73 m2/y, T2, –2.08 [95% CI, –2.52 to –1.63] and T1 –2.35 [95% CI, –2.79 to –1.91]; P=0.002). The benefit of dapagliflozin was consistent regardless of baseline ET-1, and the placebo-corrected decrease in ET-1 with dapagliflozin was 0.13 pg/mL (95% CI, 0.25–0.01; P=0.029). CONCLUSIONS: Higher baseline ET-1 concentration was independently associated with worse clinical outcomes and more rapid decline in kidney function. The benefit of dapagliflozin was consistent across the range of ET-1 concentrations measured, and treatment with dapagliflozin led to a small decrease in serum ET-1 concentration. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

Item Type:Articles
Additional Information:The DAPA-HF trial was funded by AstraZeneca. JJVM and PSJ are supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund.
Status:Early Online Publication
Glasgow Author(s) Enlighten ID:Docherty, Dr Kieran and Welsh, Dr Paul and Sattar, Professor Naveed and Jhund, Professor Pardeep and Campbell, Dr Ross and Yeoh, Su Ern and McMurray, Professor John
Authors: Yeoh, S. E., Docherty, K. F., Campbell, R. T., Jhund, P. S., Hammarstedt, A., Heerspink, H. J.L., Jarolim, P., Køber, L., Kosiborod, M. N., Martinez, F. A., Ponikowski, P., Solomon, S. D., Sjöstrand, M., Bengtsson, O., Greasley, P. J., Sattar, N., Welsh, P., Sabatine, M. S., Morrow, D. A., and McMurray, J. J.V.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Circulation
Publisher:American Heart Association
ISSN (Online):1524-4539
Published Online:11 April 2023
Copyright Holders:Copyright © 2023 The Authors.
First Published:First published in Circulation 2023
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
303944BHF Centre of ExcellenceColin BerryBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science