Choice of endpoint in kidney outcome trials: considerations from the EMPA-REG OUTCOME® trial. Issue 12 (8th September 2019)

• Record Type: Journal Article
• Authors: Perkovic, Vlado; Koitka-Weber, Audrey; Cooper, Mark E; Schernthaner, Guntram; Pfarr, Egon; Woerle, Hans J; von Eynatten, Maximilian; Wanner, Christoph
• Is Part Of: Nephrology dialysis transplantation. Volume 35:Issue 12(2020)
• Page Start: 2103
• Page End: 2111
• Publication Date: 2019-09-08
• Subjects: CKD -- clinical trial -- ESKD -- GFR -- type 2 diabetes; Nephrology -- Periodicals; Hemodialysis -- Periodicals; Kidneys -- Transplantation -- Periodicals; Hemodialysis; Kidneys -- Transplantation; Nephrology; Periodicals; 616.61
• DOI: 10.1093/ndt/gfz179
• Languages: English
• ISSNs: 0931-0509

Abstract

Abstract: Background: Doubling of serum creatinine [equivalent to 57% reduction in estimated glomerular filtration rate (eGFR)] is an established surrogate for end-stage kidney disease (ESKD); however, this endpoint necessitates lengthy follow-up and large sample sizes in clinical trials. We explored whether alternative eGFR decline thresholds provide more feasible surrogate kidney endpoints. Methods: The study involved post hoc analysis of the EMPA-REG OUTCOME ® trial. Adults with type 2 diabetes, high cardiovascular risk and eGFR ≥30 mL/min/1.73 m 2 were assigned empagliflozin 10 mg or 25 mg ( n = 4687) or placebo ( n = 2333), on top of standard of care. We assessed composite endpoints incorporating different eGFR decline thresholds (≥30, ≥40, ≥50 or ≥57%) combined with initiation of renal replacement therapy (RRT) or renal death. This trial is registered with ClinicalTrials.gov (NCT01131676). Results: Empagliflozin versus placebo significantly lowered the risk of decline in eGFR for each threshold listed above, combined with initiation of RRT or renal death, ranging from a hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.72–0.91] for endpoints based on 30% eGFR decline to an HR of 0.37 (0.23–0.61) for endpoints based on 57% eGFR decline. Lower thresholds (e.g. 30%) were associated with higher event rates but weaker treatment effects. The time to the 95% CI of the HR falling to <1.0 decreased with increasing eGFR threshold. Conclusions: The composite of 40% decline in eGFR, ESKD or renal death appears to provide reliable results similar to the traditional 57% decline in eGFR.