The Effect of Atrasentan on Kidney and Heart Failure Outcomes by Baseline Albuminuria and Kidney Function: A
albuminuria
atrasentan
endothelin receptor antagonist
heart failure
hospitalization for heart failure
kidney outcome
urinary tract physiological phenomena
Journal
Clinical journal of the American Society of Nephrology : CJASN
ISSN: 1555-905X
Titre abrégé: Clin J Am Soc Nephrol
Pays: United States
ID NLM: 101271570
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
24
05
2021
accepted:
22
09
2021
pubmed:
3
12
2021
medline:
14
1
2023
entrez:
2
12
2021
Statut:
ppublish
Résumé
Atrasentan reduces the risk of kidney failure but increases the risk of edema and, possibly, heart failure. Patients with severe CKD may obtain greater absolute kidney benefits from atrasentan but may also be at higher risk of heart failure. We assessed relative and absolute effects of atrasentan on kidney and heart failure events according to baseline eGFR and urinary albumin-creatinine ratio (UACR) in a The effect of atrasentan versus placebo in 3668 patients with type 2 diabetes and CKD with elevated albuminuria was examined in the SONAR trial. We used Cox proportional hazards regression analysis to study effects on the primary kidney outcome (composite of doubling of serum creatinine, kidney failure, or kidney death) and heart failure hospitalization across subgroups of eGFR (<30, ≥30-45, and ≥45 ml/min per 1.73 m Atrasentan reduced the relative risk of the primary kidney outcome (hazard ratio, 0.71; 95% confidence interval, 0.58 to 0.88) consistently across all subgroups of baseline eGFR and UACR (all Atrasentan reduced the relative risk of the primary kidney outcome consistently across baseline UACR and eGFR subgroups. The absolute risk reduction was greater among patients in the lowest eGFR and highest albuminuria category who were at highest baseline risk. Conversely, the relative and absolute risks of heart failure hospitalization were similar across baseline UACR and eGFR subgroups.
Sections du résumé
BACKGROUND AND OBJECTIVES
Atrasentan reduces the risk of kidney failure but increases the risk of edema and, possibly, heart failure. Patients with severe CKD may obtain greater absolute kidney benefits from atrasentan but may also be at higher risk of heart failure. We assessed relative and absolute effects of atrasentan on kidney and heart failure events according to baseline eGFR and urinary albumin-creatinine ratio (UACR) in a
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
The effect of atrasentan versus placebo in 3668 patients with type 2 diabetes and CKD with elevated albuminuria was examined in the SONAR trial. We used Cox proportional hazards regression analysis to study effects on the primary kidney outcome (composite of doubling of serum creatinine, kidney failure, or kidney death) and heart failure hospitalization across subgroups of eGFR (<30, ≥30-45, and ≥45 ml/min per 1.73 m
RESULTS
Atrasentan reduced the relative risk of the primary kidney outcome (hazard ratio, 0.71; 95% confidence interval, 0.58 to 0.88) consistently across all subgroups of baseline eGFR and UACR (all
CONCLUSIONS
Atrasentan reduced the relative risk of the primary kidney outcome consistently across baseline UACR and eGFR subgroups. The absolute risk reduction was greater among patients in the lowest eGFR and highest albuminuria category who were at highest baseline risk. Conversely, the relative and absolute risks of heart failure hospitalization were similar across baseline UACR and eGFR subgroups.
Identifiants
pubmed: 34853062
pii: 01277230-202112000-00011
doi: 10.2215/CJN.07340521
pmc: PMC8729501
doi:
Substances chimiques
Atrasentan
V6D7VK2215
Banques de données
ClinicalTrials.gov
['NCT01858532']
Types de publication
Randomized Controlled Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1824-1832Informations de copyright
Copyright © 2021 by the American Society of Nephrology.
Références
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345: 851–860, 2001
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving H-H, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345: 861–869, 2001
Jafar TH, Schmid CH, Landa M, Giatras I, Toto R, Remuzzi G, Maschio G, Brenner BM, Kamper A, Zucchelli P, Becker G, Himmelmann A, Bannister K, Landais P, Shahinfar S, de Jong PE, de Zeeuw D, Lau J, Levey AS: Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med 135: 73–87, 2001
Rossing P, Hommel E, Smidt UM, Parving H-H: Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment. Diabetologia 37: 511–516, 1994
Remuzzi G, Ruggenenti P, Perna A, Dimitrov BD, de Zeeuw D, Hille DA, Shahinfar S, Carides GW, Brenner BM; RENAAL Study Group: Continuum of renoprotection with losartan at all stages of type 2 diabetic nephropathy: A post hoc analysis of the RENAAL trial results. J Am Soc Nephrol 15: 3117–3125, 2004
Heerspink HJL, Parving H-H, Andress DL, Bakris G, Correa-Rotter R, Hou F-F, Kitzman DW, Kohan D, Makino H, McMurray JJV, Melnick JZ, Miller MG, Pergola PE, Perkovic V, Tobe S, Yi T, Wigderson M, de Zeeuw D; SONAR Committees and Investigators: Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): A double-blind, randomised, placebo-controlled trial. Lancet 393: 1937–1947, 2019
Mann JFE, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, Viberti G; ASCEND Study Group: Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 21: 527–535, 2010
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group: KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Available at https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf . Accessed November 3, 2021
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351: 1296–1305, 2004
Heerspink HJL, Andress DL, Bakris G, Brennan JJ, Correa-Rotter R, Dey J, Hou FF, Kitzman DW, Kohan D, Makino H, McMurray J, Perkovic V, Tobe S, Wigderson M, Parving HH, de Zeeuw D: Rationale and protocol of the Study of Diabetic Nephropathy with AtRasentan (SONAR) trial: A clinical trial design novel to diabetic nephropathy. Diabetes Obes Metab 20: 1369–1376, 2018
Heerspink HJL, Andress DL, Bakris G, Brennan JJ, Correa-Rotter R, Hou FF, Kitzman DW, Kohan D, Makino H, McMurray J, Perkovic V, Tobe S, Wigderson M, Yi T, Parving HH, de Zeeuw D: Baseline characteristics and enrichment results from the SONAR trial. Diabetes Obes Metab 20: 1829–1835, 2018
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro 3rd AF, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration): A new equation to estimate glomerular filtration rate. Ann Intern Med 150: 604–612, 2009
Altman DG, Andersen PK: Calculating the number needed to treat for trials where the outcome is time to an event. BMJ 319: 1492–1495, 1999
Schwarzer G, Carpenter J, Rücker G: Meta-Analysis with R (Use-R!), 2015. Available at: http://meta-analysis-with-r.org/ . Accessed August 1, 2020
Viechtbauer W: Conducting meta-analyses in R with the Metafor package. J Stat Softw 36: 1–48, 2010
Therneau TM: A Package for Survival Analysis in S. Version 2, 2015. Available at: https://cran.r-project.org/package=survival . Accessed August 1, 2020
Therneau TM, Grambsch PM: Modeling Survival Data: Extending the {C}ox Model, New York, Springer, 2000
Kohan DE, Lambers Heerspink HJ, Coll B, Andress D, Brennan JJ, Kitzman DW, Correa-Rotter R, Makino H, Perkovic V, Hou FF, Remuzzi G, Tobe SW, Toto R, Parving HH, de Zeeuw D: Predictors of atrasentan-associated fluid retention and change in albuminuria in patients with diabetic nephropathy. Clin J Am Soc Nephrol 10: 1568–1574, 2015
Hoekman J, Lambers Heerspink HJ, Viberti G, Green D, Mann JFE, de Zeeuw D: Predictors of congestive heart failure after treatment with an endothelin receptor antagonist. Clin J Am Soc Nephrol 9: 490–498, 2014
Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, Kolkhof P, Nowack C, Schloemer P, Joseph A, Filippatos G; FIDELIO-DKD Investigators: Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 383: 2219–2229, 2020
Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators: Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 380: 2295–2306, 2019
Shlipak MG, Tummalapalli SL, Boulware LE, Grams ME, Ix JH, Jha V, Kengne AP, Madero M, Mihaylova B, Tangri N, Cheung M, Jadoul M, Winkelmayer WC, Zoungas S; Conference Participants: The case for early identification and intervention of chronic kidney disease: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 99: 34–47, 2021