Kai-Uwe Eckardt1, Rajiv Agarwal1, Ahmad Aswad1, Ahmed Awad1, Geoffrey A Block1, Marcelo R Bacci1, Youssef M K Farag1, Steven Fishbane1, Harold Hubert1, Alan Jardine1, Zeeshan Khawaja1, Mark J Koury1, Bradley J Maroni1, Kunihiro Matsushita1, Peter A McCullough1, Eldrin F Lewis1, Wenli Luo1, Patrick S Parfrey1, Pablo Pergola1, Mark J Sarnak1, Bruce Spinowitz1, James Tumlin1, Dennis L Vargo1, Kimberly A Walters1, Wolfgang C Winkelmayer1, Janet Wittes1, Rafal Zwiech1, Glenn M Chertow1. 1. From the Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin (K.-U.E.); the Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis (R.A.); Gonzalez M.D. and Aswad M.D. Health Care Services, Miami (A. Aswad); Clinical Research Consultants, Kansas City, MO (A. Awad); U.S. Renal Care, Plano (G.A.B.), Baylor University Medical Center, Baylor Heart and Vascular Hospital, Baylor Heart and Vascular Institute, Dallas (P.A.M.), Renal Associates, Division of Nephrology, University of Texas Health Science Center at San Antonio, San Antonio (P.P.), and the Section of Nephrology, Baylor College of Medicine, Houston (W.C.W.) - all in Texas; Praxis Medical Research, and the Department of Medicine, Division of General Practice, Faculdade de Medicina do ABC, São Paulo (M.R.B.); Akebia Therapeutics, Cambridge (Y.M.K.F., Z.K., B.J.M., W.L., D.L.V.), and the Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston (M.J.S.) - both in Massachusetts; the Division of Nephrology, Department of Medicine, Hofstra Northwell School of Medicine, Great Neck (S.F.), and the Division of Nephrology, New York Presbyterian, Queens (B.S.) - both in New York; Nephrology Associates, Augusta (H.H.), and Emory University School of Medicine, Atlanta (J.T.) - both in Georgia; the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.J.); the Department of Medicine, Vanderbilt University Medical Center, Nashville (M.J.K.); the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore (K.M.); Stanford University School of Medicine, Palo Alto, CA (E.F.L., G.M.C.); the Department of Medicine, Memorial University, St. John's, NL, Canada (P.S.P.); Statistics Collaborative, Washington, DC (K.A.W., J.W.); and the Department of Kidney Transplantation-Dialysis Department, Barlicki Memorial Teaching Hospital No. 1, Medical University of Lodz, Lodz, Poland (R.Z.).
Abstract
BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS:A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).
RCT Entities:
BACKGROUND:Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).
Authors: Pengfei Sun; Nitin Kumar; Adrienne Tin; Jing Zhao; Michael R Brown; Zesen Lin; Min-Lee Yang; Qiwen Zheng; Jia Jia; Lawrence F Bielak; Bing Yu; Eric Boerwinkle; Kristina L Hunker; Josef Coresh; Y Eugene Chen; Yong Huo; Sharon L R Kardia; Rami Khoriaty; Xiang Zhou; Alanna C Morrison; Yan Zhang; Santhi K Ganesh Journal: Hypertension Date: 2021-09-07 Impact factor: 10.190
Authors: Patrizia Natale; Suetonia C Palmer; Allison Jaure; Elisabeth M Hodson; Marinella Ruospo; Tess E Cooper; Deirdre Hahn; Valeria M Saglimbene; Jonathan C Craig; Giovanni Fm Strippoli Journal: Cochrane Database Syst Rev Date: 2022-08-25