Clinical Pearls & Morning Reports
Published April 28, 2021
Chertow et al. recently reported the results of two trials that examined the cardiovascular safety and hematologic efficacy of vadadustat, as compared with darbepoetin alfa, a commonly prescribed erythropoiesis-stimulating agent (ESA), in patients with non–dialysis-dependent chronic kidney disease (NDD-CKD); one trial involved patients with anemia who had not received previous treatment with ESAs and the other involved patients with anemia actively treated with ESAs. Read the NEJM Original Article here.
Q: How is the anemia that develops as a complication of CKD usually treated?
A: Anemia is a common complication of CKD. Among patients with moderate-to-advanced NDD-CKD, the prevalence of anemia, defined as a hemoglobin concentration below 13 g per deciliter in men and below 12 g per deciliter in women, is approximately 30 to 40%. Conventional treatment of anemia in patients with NDD-CKD includes correction of iron deficiency and the provision of ESAs to maintain the hemoglobin concentration within the range of 9 to 12 g per deciliter. Treatment with ESAs reduces the need for red-cell transfusion, but an increased risk of certain cardiovascular events has been identified when hemoglobin concentrations in the near-normal range are targeted.
Q: What is vadadustat?
A: Hypoxia-inducible factor (HIF) is a transcription factor that regulates many physiological responses to hypoxia, including erythropoietin production by the liver and kidneys. HIF is regulated by oxygen-dependent proteasomal degradation, with a family of prolyl hydroxylases serving as oxygen sensors. HIF prolyl hydroxylase inhibitors comprise a new class of compounds that stabilize HIF, which in turn stimulates endogenous erythropoietin production. Vadadustat is an oral HIF prolyl hydroxylase inhibitor that is under investigation for the treatment of anemia associated with CKD.
A: The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. The pooled results from these two randomized trials involving patients with NDD-CKD showed that vadadustat did not meet its prespecified noninferiority margin with respect to MACE. A first MACE occurred in 382 of 1739 patients (22.0%) in the vadadustat group and in 344 of 1732 patients (19.9%) in the darbepoetin alfa group (hazard ratio, 1.17; 95% CI, 1.01 to 1.36). Vadadustat met its noninferiority margin with respect to hematologic efficacy in each trial.
A: Analysis of events in the current trials revealed that the higher risk that was observed among patients who had been randomly assigned to the vadadustat group than among those in the darbepoetin alfa group was due largely to an excess of nonfatal myocardial infarctions and a higher incidence of death from noncardiovascular causes. The authors could identify no explanation for the excess in noncardiovascular deaths. The cumulative incidences of pulmonary hypertension and cancer, which are theoretical consequences of HIF pathway activation, were similar in the two treatment groups.