Hiddo J Lambers Heerspink1, Misghina Weldegiorgis2, Lesley A Inker3, Ron Gansevoort4, Hans-Henrik Parving5, Jamie P Dwyer6, Hasi Mondal3, Josef Coresh7, Tom Greene8, Andrew S Levey3, Dick de Zeeuw2. 1. Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address: h.j.lambers.heerspink@umcg.nl. 2. Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 3. Division of Nephrology, Tufts Medical Center, Boston, MA. 4. Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 5. Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, and the Faculty of Health Sciences, Aarhus University, Aarhus, Denmark. 6. Department of Nephrology, Vanderbilt University School of Medicine, Nashville, TN. 7. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. 8. University of Utah, Salt Lake City, UT.
Abstract
BACKGROUND: A doubling of serum creatinine value, corresponding to a 57% decline in estimated glomerular filtration rate (eGFR), is used frequently as a component of a composite kidney end point in clinical trials in type 2 diabetes. The aim of this study was to determine whether alternative end points defined by smaller declines in eGFR would improve the statistical power of these clinical trials. STUDY DESIGN: Post hoc analyses of 2 multinational randomized controlled trials (Reduction of End Points in Non-Insulin-Dependent Diabetes With theAngiotensin II Antagonist Losartan [RENAAL] and Irbesartan Diabetic Nephropathy Trial [IDNT]) that assessed the treatment effect of the angiotensin receptor blockers (ARBs) losartan and irbesartan. SETTING & PARTICIPANTS: 1,513 (RENAAL) and 1,715 (IDNT) adult patients with type 2 diabetes and nephropathy. PREDICTOR: Established versus alternative end points defined as a confirmed doubling of serum creatinine level versus confirmed eGFR decline of 57%, 40%, 30%, or 20% as a component of a composite end point of end-stage renal disease or eGFR < 15mL/min/1.73m(2). OUTCOMES: Numbers of patients reaching end points, precision (standard error), and significance (z score) of ARB treatment effect (HR) during follow-up. RESULTS: Lesser eGFR declines resulted in a greater number of patients reaching end points in both treatment groups and lower standard error of the HR, but the effect on z score was counterbalanced by attenuation of the HR. When calculating the eGFR decline from month 3, attenuation of the HR was less pronounced. LIMITATIONS: Post hoc analysis. CONCLUSIONS: Despite increases in precision of the treatment effect, eGFR declines less than a doubling of serum creatinine value did not consistently improve statistical power of the clinical trials due to attenuation of the treatment effect. Attenuation of the treatment effect appears to be due in part to acute effects of ARBs on eGFR. These findings should be taken into account when using lesser eGFR declines as alternative end points for clinical trials.
RCT Entities:
BACKGROUND: A doubling of serum creatinine value, corresponding to a 57% decline in estimated glomerular filtration rate (eGFR), is used frequently as a component of a composite kidney end point in clinical trials in type 2 diabetes. The aim of this study was to determine whether alternative end points defined by smaller declines in eGFR would improve the statistical power of these clinical trials. STUDY DESIGN: Post hoc analyses of 2 multinational randomized controlled trials (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan [RENAAL] and IrbesartanDiabetic Nephropathy Trial [IDNT]) that assessed the treatment effect of the angiotensin receptor blockers (ARBs) losartan and irbesartan. SETTING & PARTICIPANTS: 1,513 (RENAAL) and 1,715 (IDNT) adult patients with type 2 diabetes and nephropathy. PREDICTOR: Established versus alternative end points defined as a confirmed doubling of serum creatinine level versus confirmed eGFR decline of 57%, 40%, 30%, or 20% as a component of a composite end point of end-stage renal disease or eGFR < 15mL/min/1.73m(2). OUTCOMES: Numbers of patients reaching end points, precision (standard error), and significance (z score) of ARB treatment effect (HR) during follow-up. RESULTS: Lesser eGFR declines resulted in a greater number of patients reaching end points in both treatment groups and lower standard error of the HR, but the effect on z score was counterbalanced by attenuation of the HR. When calculating the eGFR decline from month 3, attenuation of the HR was less pronounced. LIMITATIONS: Post hoc analysis. CONCLUSIONS: Despite increases in precision of the treatment effect, eGFR declines less than a doubling of serum creatinine value did not consistently improve statistical power of the clinical trials due to attenuation of the treatment effect. Attenuation of the treatment effect appears to be due in part to acute effects of ARBs on eGFR. These findings should be taken into account when using lesser eGFR declines as alternative end points for clinical trials.
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