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Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers.
- Source :
-
European journal of preventive cardiology [Eur J Prev Cardiol] 2016 May; Vol. 23 (7), pp. 758-68. Date of Electronic Publication: 2015 Jul 30. - Publication Year :
- 2016
-
Abstract
- Background: A recent phase II clinical trial (Reducing Residual Albuminuria in Subjects with Diabetes and Nephropathy with AtRasentan trial and an identical trial in Japan (RADAR/JAPAN)) showed that the endothelin A receptor antagonist atrasentan lowers albuminuria, blood pressure, cholesterol, hemoglobin, and increases body weight in patients with type 2 diabetes and nephropathy. We previously developed an algorithm, the Parameter Response Efficacy (PRE) score, which translates short-term drug effects into predictions of long-term effects on clinical outcomes.<br />Design: We used the PRE score on data from the RADAR/JAPAN study to predict the effect of atrasentan on renal and heart failure outcomes.<br />Methods: We performed a post-hoc analysis of the RADAR/JAPAN randomized clinical trials in which 211 patients with type-2 diabetes and nephropathy were randomly assigned to atrasentan 0.75 mg/day, 1.25 mg/day, or placebo. A PRE score was developed in a background set of completed clinical trials using multivariate Cox models. The score was applied to baseline and week-12 risk marker levels of RADAR/JAPAN participants, to predict atrasentan effects on clinical outcomes. Outcomes were defined as doubling serum creatinine or end-stage renal disease and hospitalization for heart failure.<br />Results: The PRE score predicted renal risk changes of -23% and -30% for atrasentan 0.75 and 1.25 mg/day, respectively. PRE scores also predicted a small non-significant increase in heart failure risk for atrasentan 0.75 and 1.25 mg/day (+2% vs. +7%). Selecting patients with >30% albuminuria reduction from baseline (responders) improved renal outcome to almost 50% risk reduction, whereas non-responders showed no renal benefit.<br />Conclusions: Based on the RADAR/JAPAN study, with short-term changes in risk markers, atrasentan is expected to decrease renal risk without increased risk of heart failure. Within this population albuminuria responders appear to contribute to the predicted improvements, whereas non-responders showed no benefit. The ongoing hard outcome trial (SONAR) in type 2 diabetic patients with >30% albuminuria reduction to atrasentan will allow us to assess the validity of these predictions.<br /> (© The European Society of Cardiology 2015.)
- Subjects :
- Aged
Atrasentan
Biomarkers metabolism
Diabetes Mellitus, Type 2 metabolism
Dose-Response Relationship, Drug
Endothelin Receptor Antagonists administration & dosage
Female
Follow-Up Studies
Heart Failure complications
Heart Failure physiopathology
Humans
Kidney physiopathology
Male
Middle Aged
Renal Insufficiency, Chronic etiology
Renal Insufficiency, Chronic physiopathology
Time Factors
Treatment Outcome
Diabetes Mellitus, Type 2 complications
Glomerular Filtration Rate drug effects
Heart Failure drug therapy
Pyrrolidines administration & dosage
Renal Insufficiency, Chronic prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 2047-4881
- Volume :
- 23
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- European journal of preventive cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 26229089
- Full Text :
- https://doi.org/10.1177/2047487315598709