Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non- Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PRO2TECT Randomized Clinical Trial of ESA-Treated Patients

Authors

Patrick S Parfrey
Steven K Burke
Glenn M Chertow
Kai-Uwe Eckardt
Alan G Jardine
Eldrin F Lewis
Wenli Luo
Kunihiro Matsushita
Peter A McCullough
Todd Minga
Wolfgang C Winkelmayer

Publication Date

7-1-2023

Journal

Kidney Medicine

DOI

10.1016/j.xkme.2023.100667

PMID

37427292

PMCID

PMC10329165

PubMedCentral® Posted Date

5-12-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Anemia, chronic kidney disease, hypoxia-inducible factor, vadadustat, darbepoetin alfa

Abstract

RATIONALE & OBJECTIVE: In the PRO

STUDY DESIGN: Phase 3, global, open-label, randomized, active-controlled clinical trial.

SETTING & PARTICIPANTS: A total of 1,725 erythropoiesis-stimulating agent (ESA)-treated patients with anemia and NDD-CKD.

INTERVENTION: 1:1 randomization to receive vadadustat or darbepoetin alfa.

OUTCOMES: The primary safety end point was the time to first MACE.

RESULTS: At baseline, patients in Europe (n=444) were primarily treated with darbepoetin alfa, showed higher proportions on low ESA doses (/kg/wk epoetin alfa equivalents) with a hemoglobin concentration of ≥10 g/dL compared with patients in the US (n=665) and non-US/non-Europe (n=614) regions. The MACE rates per 100 person-years in the 3 vadadustat groups across regions were 14.5 in the US, 11.6 in Europe, and 10.0 in the non-US/non-Europe groups, whereas event rates in the darbepoetin alfa group were considerably lower in Europe than in the US and non-US/non-Europe groups (6.7 vs 13.3 and 10.5, respectively). The overall hazard ratio for MACE for vadadustat vs darbepoetin alpha was 1.16; 95% CI, 0.93-1.45, but varied by geographical region, with a greater hazard ratio seen in Europe (US, 1.07; 95% CI, 0.78-1.46; Europe, 2.05; 95% CI, 1.24-3.39; non-US/non-Europe, 0.91; 95% CI, 0.60-1.37); interaction between study treatment and geographical region,

LIMITATIONS: Several analyses are exploratory.

CONCLUSIONS: In this trial, there was a low risk of MACE in the darbepoetin alfa group in Europe. Patients in Europe were generally on low doses of ESA, with hemoglobin already within target range. The low risk of MACE may have been related to a limited need to switch and titrate darbepoetin alfa compared with the non-US/non-Europe group.

FUNDING: Akebia Therapeutics, Inc.

Comments

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02680574

Associated Data