Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis
In the phase 3 INNO2VATE trials, the oral HIF-prolyl hydroxylase inhibitor vadadustat was noninferior to darbepoetin alfa for both cardiovascular safety and hemoglobin efficacy in patients with anemia undergoing dialysis.
Background
Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates endogenous erythropoietin production, offering a potential alternative to injectable erythropoiesis-stimulating agents for anemia in dialysis-dependent CKD.
Study design
Two randomized, open-label, noninferiority phase 3 trials (INNO2VATE) compared vadadustat with darbepoetin alfa in 3923 patients with anemia and incident or prevalent dialysis-dependent CKD. The primary safety endpoint was time to first major adverse cardiovascular event (MACE: death, nonfatal MI, or nonfatal stroke; noninferiority margin 1.25); the efficacy endpoints were mean hemoglobin change at weeks 24–36 and 40–52 (noninferiority margin −0.75 g/dL).
Key findings
A first MACE occurred in 18.2% of the vadadustat group versus 19.3% with darbepoetin alfa (hazard ratio 0.96, 95% CI 0.83–1.11), meeting noninferiority for cardiovascular safety. Between-group differences in hemoglobin change were small and within the noninferiority margin (e.g., −0.17 and −0.18 g/dL in the prevalent-dialysis trial). Serious adverse event rates were similar to (and numerically lower than) darbepoetin alfa.
Clinical implications
Vadadustat is an effective oral option for managing anemia in dialysis patients, achieving hemoglobin targets comparable to darbepoetin alfa without an increased cardiovascular safety signal in this population — supporting its role where an oral ESA alternative is desired (notably, results differed in the non-dialysis CKD population studied separately).
Category
Research
Source
The New England Journal of Medicine
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