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Effects of Sacubitril/Valsartan Versus Irbesartan in Patients with Chronic Kidney Disease: A Randomised Double-Blind Trial

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posted on 2019-06-17, 13:33 authored by R Haynes, PK Judge, N Staplin, WG Herrington, BC Storey, A Bethel, L Bowman, N Brunskill, P Cockwell, M Hill, PA Kalra, JJV McMurray, M Taal, DC Wheeler, MJ Landray, C Baigent
Background: Sacubitril/valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction, but its effects on kidney function and cardiac biomarkers in people with moderate to severe chronic kidney disease are unknown. Methods: The UK HARP-III trial (United Kingdom Heart and Renal Protection-III), a randomized double-blind trial, included 414 participants with an estimated glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m2 who were randomly assigned to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily. The primary outcome was measured GFR at 12 months using ANCOVA with adjustment for each individual’s baseline measured GFR. All analyses were by intention to treat. Results: In total, 207 participants were assigned to sacubitril/valsartan and 207 to irbesartan. Baseline measured GFR was 34.0 (SE, 0.8) and 34.7 (SE, 0.8) mL/min/1.73 m2, respectively. At 12 months, there was no difference in measured GFR: 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (SE, 0.5) mL/min/1.73 m2 among those assigned irbesartan; difference, -0.1 (0.7) mL/min/1.73 m2. Effects were similar in all prespecified subgroups. There was also no significant difference in estimated GFR at 3, 6, 9, or 12 months and no clear difference in urinary albumin:creatinine ratio between treatment arms (study average difference, -9%; 95% CI, -18 to 1). However, compared with irbesartan, allocation to sacubitril/valsartan reduced study average systolic and diastolic blood pressure by 5.4 (95% CI, 3.4–7.4) and 2.1 (95% CI, 1.0–3.3) mm Hg and levels of troponin I and N terminal of prohormone brain natriuretic peptide (tertiary end points) by 16% (95% CI, 8–23) and 18% (95% CI, 11–25), respectively. The incidence of serious adverse events (29.5% versus 28.5%; rate ratio, 1.07; 95% CI, 0.75–1.53), nonserious adverse reactions (36.7% versus 28.0%; rate ratio, 1.35; 95% CI, 0.96–1.90), and potassium ≥5.5 mmol/L (32% versus 24%, P=0.10) was not significantly different between randomized groups. Conclusions: Over 12 months, sacubitril/valsartan has similar effects on kidney function and albuminuria to irbesartan, but it has the additional effect of lowering blood pressure and cardiac biomarkers in people with chronic kidney disease. Clinical Trial Registration: URL: http://www.isrctn.com. Unique identifier: ISRCTN11958993.

Funding

The UK HARP-III trial was designed, conducted, and analyzed by the MRC Population Health Research Unit, which is part of the Clinical Trial Service Unit and Epidemiological Studies Unit. The University of Oxford was the independent regulatory sponsor for the study. The study was funded by a grant to the University of Oxford from Novartis (the manufacturer of sacubitril/valsartan). The funder had no involvement in the study conduct, analysis, or decision to submit for publication. The trial was supported by the Medical Research Council (which funds the Medical Research Council Population Health Research Unit in a strategic partnership with the University of Oxford) and the National Institute for Health Research Clinical Research Network.

History

Citation

Circulation, 2018;138:1505–1514

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Infection, Immunity and Inflammation

Version

  • VoR (Version of Record)

Published in

Circulation

Publisher

American Heart Association, Lippincott, Williams & Wilkins

issn

0009-7322

eissn

1524-4539

Acceptance date

2018-06-22

Copyright date

2018

Available date

2019-06-17

Publisher version

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.034818

Notes

The online-only Data Supplement, podcast, and transcript are available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.118.034818.

Language

en

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