1. Vadadustat was shown to be non-inferior to darbepoetin alfa in cardiovascular safety for patients with anemia and dialysis-dependent chronic kidney disease (DD-CKD).
2. Vadadustat was shown to present comparable efficacy in normalizing hemoglobin concentration compared to darbepoetin alfa in the patient population.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Chronic kidney disease is commonly associated with anemia, due to erythropoietin decline, resulting in reduced quality of life and increase red-cell transfusions. Darbepoetin alfa mimics erythropoietin activity and is the standard of care for treating anemia in this patient population. However, darbepoetin alfa increases the risk of cardiovascular events and death. As such, this study examined the hematologic efficacy and cardiovascular safety of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, in patients with anemia and DD-CKDs compared to darbepoetin alfa. The study determined vadadustat exhibited comparable time to the first occurrence of a major adverse cardiovascular event (MACE) and hospitalization rate compared to darbepoetin alfa. Furthermore, vadadustat showed similar improvements in hemoglobin compared to darbepoetin alfa. The study was limited by open-label design preventing assessment of patient-reported symptoms. Nonetheless, the study’s results are significant, as this study demonstrated the safety and efficacy of vadadustat to manage anemia in DD-CKD patients.
In-Depth [randomized controlled trial]: This study pooled results from two randomized controlled trials, enrolling 369 patients with incident DD-CKD and 3554 with prevalent DD-CKD. Adult patients were included if they were undergoing dialysis, had at least 100ng/mL serum ferritin, and at least 20% transferrin saturation. Patients were excluded if they had anemia due to causes other than CKD, uncontrolled hypertension, or a recent cardiovascular event. Patients were randomized in a 1:1 ratio to receive either vadadustat or darbepoetin alfa, respectively. Dosage was adjusted to achieve hemoglobin targets (according to regional guidelines). The primary safety endpoint was time to the first occurrence of a MACE, which was defined as a composite endpoint of death from any cause, nonfatal myocardial infarction, or a nonfatal stroke. The primary efficacy endpoint was the mean change in hemoglobin level from baseline during the primary (weeks 24-36) and secondary (weeks 40-52) evaluation periods. The cumulative probabilities of a first MACE were comparable between vadadustat (18.2%) and darbepoetin alfa (19.4%) (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). In the incident DD-CKD trial, the mean between-group differences in the change in hemoglobin concentration were -0.31 g/dL (standard deviation [SD], 0.11; 95% CI, -0.53 to -0.10) at primary evaluation and -0.07 g/dL (SD, 0.13; 95% CI, -0.34 to 0.19) at secondary evaluation. In the prevalent DD-CKD trial, the mean between-group differences in the change in hemoglobin concentration were -0.17g/dL (SD, 0.03; 95% CI, -0.23 to -0.10) at primary evaluation and -0.18g/dL (SD, 0.04; 95% CI, -0.25 to -0.12) at secondary evaluation. Overall, vadadustat was non-inferior to darbepoetin alfa in safety and efficacy profiles for the management of anemia in DD-CKD.
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