Vadadustat in Patients with Anemia and Non–Dialysis-Dependent CKD

SPS commentary:

This is one of two articles in the New England Journal of Medicine that describe trials in which vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production, was compared with active therapy with darbepoetin alfa.

The second article is also based on the results of pooled analyses of two open label non-inferiority trials (n=3923) but in patients undergoing dialysis, which found vadadustat noninferior to darbepoetin alfa with respect to CV safety (first major adverse CV event in 18.2% and 19.3%, respectively; HR 0.96; 95% CI, 0.83 to 1.11) and correction and maintenance of haemoglobin levels.

An editorial notes that noninferiority trials are generally used to show that a predetermined minimum level of efficacy has been achieved with a new agent, as compared with current therapy, and that the new agent provides at least similar benefit. If the new treatment is shown to be noninferior to the current therapy (in this case, an ESA), evidence of additional benefit, lower risk of adverse effects, cost savings, or better adherence or convenience for patients is still needed. It stresses that noninferior does not mean equivalent, but rather that one agent is not significantly worse than the other. It suggests that these current data are convincing that vadadustat is effective in increasing haemoglobin concentrations in both dialysis-dependent and non–dialysis dependent populations but are less convincing with respect to safety. The issues raised in these trials should provide the stimulus to answer critical questions regarding goals of therapy, risks, and benefits, with trials specifically designed to do so.