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

Haynes, Richard; Judge, Parminder K.; Staplin, Natalie; Herrington, William G.; Storey, Benjamin C.; Bethel, Angelyn; Bowman, Louise; Brunskill, Nigel; Cockwell, Paul; Hill, Michael; Kalra, Philip A.; McMurray, John J. V.; Taal, Maarten; Wheeler, David C.; Landray, Martin J.; Baigent, Colin


Richard Haynes

Parminder K. Judge

Natalie Staplin

William G. Herrington

Benjamin C. Storey

Angelyn Bethel

Louise Bowman

Nigel Brunskill

Paul Cockwell

Michael Hill

Philip A. Kalra

John J. V. McMurray

David C. Wheeler

Martin J. Landray

Colin 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: UK HARP-III was a randomised double-blind trial which included 414 participants with an estimated glomerular filtration rate (GFR) 20-60 mL/min/1.73m2 who were randomly assigned to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily. The primary outcome was measured GFR (mGFR) at 12 months using analysis of covariance with adjustment for each individual's baseline mGFR. All analyses were by intention to treat. This trial is registered at ISRCTN11958993.
Results: 207 participants were assigned to sacubitril/valsartan and 207 to irbesartan. Baseline mGFR was 34.0 (0.8) and 34.7 (0.8) mL/min/1.73m2 respectively. At 12 months there was no difference in measured GFR: 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (0.5) mL/min/1.73m2 among those assigned irbesartan; difference -0.1 (0.7) mL/min/1.73m2 Effects were similar in all pre-specified 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 to 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) mmHg, and levels of troponin I and N-terminal of pro-hormone brain natriuretic peptide (tertiary endpoints) by 16% (95% CI 8-23) and 18% (95% CI 11-25), respectively. The incidence of serious adverse events (29.5% vs 28.5%; rate ratio [RR] 1.07, 95% CI 0.75-1.53), non-serious adverse reactions (36.7% vs 28.0%; RR 1.35, 95% CI 0.96-1.90) and potassium ≥ 5.5 mmol/L (32% vs 24%; p=0.10) were not significantly different between randomized groups.
Conclusions:Over 12 months, sacubitril/valsartan has similar effects on kidney function and albuminuria to irbesartan, but has the additional effect of lowering blood pressure and cardiac biomarkers in people with chronic kidney disease.


Haynes, R., Judge, P. K., Staplin, N., Herrington, W. G., Storey, B. C., Bethel, A., …Baigent, C. (2018). Effects of Sacubitril/Valsartan Versus Irbesartan in Patients With Chronic Kidney Disease: A Randomized Double-Blind Trial. Circulation, 138(15), 1505-1514.

Journal Article Type Article
Acceptance Date Jun 22, 2018
Online Publication Date Oct 9, 2018
Publication Date Oct 9, 2018
Deposit Date Oct 8, 2018
Publicly Available Date Apr 10, 2019
Journal Circulation
Print ISSN 0009-7322
Electronic ISSN 1524-4539
Publisher American Heart Association
Peer Reviewed Peer Reviewed
Volume 138
Issue 15
Pages 1505-1514
Keywords Physiology (medical); Cardiology and Cardiovascular Medicine
Public URL
Publisher URL


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