PracticeUpdate Conference Series ISN WCN 2019

primary endpoint, which was the compos- ite of doubling of creatinine or end-stage renal disease ESRD (defined as an eGFR 15 mL/min/1.73 m 2 confirmed at 90 days, receiving chronic dialysis, renal transplan- tation, or renal death), occurred in 6.0% of those on active therapy versus 7.9% of those on placebo (hazard ratio 0.65; 5% confidence interval 0.49 to 0.88; P = .005). Similarly, when comparing active therapy to placebo, the hazard ratio for time to 50% eGFR reduction was 0.73 (95% CI 0.55–0.98; P = .038), and the time to the composite cardiorenal outcome of doubling of serum creatinine or ESRD or cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was 0.80 (95% CI 0.54–0.99; P = .049). The eGFR slope over the study period was –2.4 mL/min/1.73 m 2 /year (95% CI –2.7 to –2.1) with active therapy and –3.1 (95% CI –3.4 to –2.8) with placebo, which was significantly different at P = .0005. There were no differences between the two groups with respect to hospi- talization for heart failure or all-cause mortality, although heart failure rates were numerically higher in the treatment arm. Subgroup analyses did not reveal any significant differences in treatment effects. Serious adverse events occurred at a rate of 36.3% with active therapy and 32.3% with placebo (P = .049). This difference was largely driven by higher rates of hypervolemia or fluid retention and ane- mia in the treatment group. Dr. Correa-Rotter concluded in his pres- entation that, “If confirmed, endothelin antagonists like atrasentan could be beneficial for subpopulations of patients who are carefully selected in relation to those who present an adequate response to a good surrogate marker that predicts the long-term benefit, such as albuminu- ria, as we have seen in this study, and excluding patients who either predict a bad response or who may have specific contraindications, like sodium retention or heart failure.” “The 35% reduction in renal events as observed in the SONAR study would con- siderably reduce the residual risk in the studied diabetes patients,” he continued. “In terms of safety, the increased event rate for heart failure, albeit statistically nonsignificant, needs attention and needs to be weighed against the benefits and individualized.”

" If confirmed, endothelin antagonists like atrasentan could be beneficial for subpopulations of patients who are carefully selected in relation to those who present an adequate response to a good surrogate marker that predicts the long-term benefit, such as albuminuria … and excluding patients who either predict a bad response or who may have specific contraindications, like sodium retention or heart failure. "

Among the patients who remained in the trial, the 2648 who responded to atrasentan with a ≥30% UACR reduction were termed “responders” and the 1020 whose UACR reduction was >30% were termed “non-responders”. Both groups of patients were randomized to 0.75 mg of atrasentan or placebo. During the enrichment phase of the trial, there was an overall 30% reduction in albuminuria, including 52% in respond- ers and 8% in non-responders. There was also an overall 0.6 kg body weight increase, with no significant difference in body weight increase between respond- ers and non-responders.

Among the 2648 responders who entered the double-blind phase of the trial, 86% of those on active therapy and 85% of those on placebo remained in the trial, which was stopped prematurely in November 2017 because the 6% predicted event rate was actually closer to 3%. Still, the investigators continued to monitor events for an additional 6 months, which gave them a total of 185 events and 80% power to detect a 35% effect difference. In the responder group, baseline char- acteristics were similar between those on placebo and those on active therapy. There was a 33% difference in rate of albuminuria compared with placebo. The

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WCN 2019 • PRACTICEUPDATE CONFERENCE SERIES 11