title: Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers.
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.
  
  
  METHODS
  We used the PRE score on data from the RADAR/JAPAN study to predict the effect of atrasentan on renal and heart failure outcomes.
  
  
  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.
  
  
  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.
  
  
  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.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Bauke
authors.initials: B
authors.lastname: Schievink
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Smink
authors.affiliation: Renal Clinical Development, Abbvie, North Chicago, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Andress
authors.affiliation: Renal Clinical Development, Abbvie, North Chicago, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Brennan
authors.affiliation: Renal Clinical Development, Abbvie, North Chicago, USA.
authors.forename: Blai
authors.initials: B
authors.lastname: Coll
authors.affiliation: National Medical Science and Nutrition Institute Salvador Zubiran, Mexico City, Mexico.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Correa-Rotter
authors.affiliation: Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Kohan
authors.affiliation: Cardiology Section, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, USA.
authors.forename: Dalane W
authors.initials: DW
authors.lastname: Kitzman
authors.affiliation: Okayama University Hospital, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
authors.affiliation: Department of Medical Endocrinology Rigshospitalet, University Hospital of Copenhagen, Denmark.
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.affiliation: The George Institute for International Health, The University of Sydney, Australia.
authors.forename: Vlado
authors.initials: V
authors.lastname: Perkovic
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Bergamo, Italy; Unit of Nephrology, Dialysis and Transplantation, AO Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.affiliation: Sunnybrook Health Sciences Center, Toronto, Canada.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Tobe
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Toto
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, The Netherlands.
authors.forename: Jarno
authors.initials: J
authors.lastname: Hoekman
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands H.J.Lambers.Heerspink@umcg.nl.
authors.forename: Hiddo J
authors.initials: HJ
authors.lastname: Lambers Heerspink
mesh_terms: D000368:Aged; D000077868:Atrasentan; D015415:Biomarkers / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000008:administration & dosage*; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D000077868:Atrasentan
keywords: Type 2 diabetes; albuminuria; atrasentan; cardiovascular disease; renal disease