Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers. (May 2016)

• Record Type: Journal Article
• Authors: Schievink, Bauke; de Zeeuw, Dick; Smink, Paul A; Andress, Dennis; Brennan, John J; Coll, Blai; Correa-Rotter, Ricardo; Hou, Fan Fan; Kohan, Donald; Kitzman, Dalane W; Makino, Hirofumi; Parving, Hans-Henrik; Perkovic, Vlado; Remuzzi, Giuseppe; Tobe, Sheldon; Toto, Robert; Hoekman, Jarno; Lambers Heerspink, Hiddo J
• Is Part Of: European journal of preventive cardiology. Volume 23:Number 7(2016)
• Page Start: 758
• Page End: 768
• Publication Date: 2016-05
• Subjects: Type 2 diabetes -- renal disease -- cardiovascular disease -- albuminuria -- atrasentan; Cardiovascular system -- Diseases -- Prevention -- Periodicals; Cardiac patients -- Rehabilitation -- Periodicals; 616.12
• DOI: 10.1177/2047487315598709
• Languages: English
• ISSNs: 2047-4873

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. 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. 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.