Hiddo J L Heerspink1, Di Xie2, George Bakris3, Ricardo Correa-Rotter4, Fan-Fan Hou2, Dalane W Kitzman5, Donald Kohan6, Hirofumi Makino7, John J V McMurray8, Vlado Perkovic9, Peter Rossing10,11, Hans-Henrik Parving12,13, Dick de Zeeuw14. 1. Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands h.j.lambers.heerspink@umcg.nl. 2. Division of Nephrology, Nanfang Hospital, Guangzhou, China. 3. American Society Hypertension Comprehensive Hypertension Center, University of Chicago Medicine and Biological Sciences, Chicago, Illinois. 4. National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico. 5. Wake Forest School of Medicine, Winston-Salem, North Carolina. 6. Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah. 7. Okayama University, Okayama, Japan. 8. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. 9. University of New South Wales, Sydney, Australia. 10. Steno Diabetes Center Copenhagen, Gentofte, Denmark. 11. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 12. Department of Medical Endocrinology, University of Copenhagen, Copenhagen, Denmark. 13. Faculty of Health Science, Aarhus University, Aarhus, Denmark. 14. Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands.
Abstract
BACKGROUND: Whether early reduction in albuminuria with atrasentan treatment predicts its long-term kidney-protective effect is unknown. METHODS: To assess the long-term effects on kidney outcomes of atrasentan versus placebo in the SONAR trial, we enrolled patients who had type 2 diabetes and CKD (stage 2-4) and a urinary albumin creatinine ratio (UACR) of 300-5000 mg/g; participants were receiving maximum tolerated renin-angiotensin system inhibition. After 6 weeks exposure to 0.75 mg/day atrasentan (enrichment period), participants were randomized (stratified by UACR response during enrichment, ranging from ≤60% to >0%) to continue atrasentan or transition to placebo. Primary kidney outcome was a composite of sustained serum creatinine doubling or ESKD. RESULTS: UACR response to atrasentan during enrichment persisted throughout the double-blind treatment phase and predicted the primary kidney outcome, whereas UACR levels with placebo remained below pre-enrichment values in the two highest UACR response strata, and exceeded pre-enrichment values in the two lowest strata. As a result, early UACR response to atrasentan during enrichment was also associated with the primary kidney outcome during placebo. Accordingly, the predictive effect of early albuminuria changes during atrasentan was eliminated after placebo correction, leading to a consistent relative risk reduction for the primary kidney outcome with atrasentan compared with placebo, irrespective of the initial UACR response. The difference between atrasentan and placebo in UACR during double-blind treatment was also consistent across UACR response strata. CONCLUSIONS: Our findings do not support UACR response as a causal predictor of atrasentan's treatment effect. However, the variable trajectory in UACR with placebo, aspects of the trial design, day-to-day variability in albuminuria, and potential long-lasting effects of atrasentan may have contributed.
BACKGROUND: Whether early reduction in albuminuria with atrasentan treatment predicts its long-term kidney-protective effect is unknown. METHODS: To assess the long-term effects on kidney outcomes of atrasentan versus placebo in the SONAR trial, we enrolled patients who had type 2 diabetes and CKD (stage 2-4) and a urinary albumin creatinine ratio (UACR) of 300-5000 mg/g; participants were receiving maximum tolerated renin-angiotensin system inhibition. After 6 weeks exposure to 0.75 mg/day atrasentan (enrichment period), participants were randomized (stratified by UACR response during enrichment, ranging from ≤60% to >0%) to continue atrasentan or transition to placebo. Primary kidney outcome was a composite of sustained serum creatinine doubling or ESKD. RESULTS: UACR response to atrasentan during enrichment persisted throughout the double-blind treatment phase and predicted the primary kidney outcome, whereas UACR levels with placebo remained below pre-enrichment values in the two highest UACR response strata, and exceeded pre-enrichment values in the two lowest strata. As a result, early UACR response to atrasentan during enrichment was also associated with the primary kidney outcome during placebo. Accordingly, the predictive effect of early albuminuria changes during atrasentan was eliminated after placebo correction, leading to a consistent relative risk reduction for the primary kidney outcome with atrasentan compared with placebo, irrespective of the initial UACR response. The difference between atrasentan and placebo in UACR during double-blind treatment was also consistent across UACR response strata. CONCLUSIONS: Our findings do not support UACR response as a causal predictor of atrasentan's treatment effect. However, the variable trajectory in UACR with placebo, aspects of the trial design, day-to-day variability in albuminuria, and potential long-lasting effects of atrasentan may have contributed.
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