Safety and Efficacy of Vadadustat for the Treatment of CKD-Related Anemia within and outside the United States

Abstract

Key Points:

1. Among patients with dialysis-dependent CKD, safety and efficacy of vadadustat and darbepoetin alfa in the United States and outside the United States were similar.

2. Among US patients with non–dialysis-dependent CKD, safety outcomes were similar; the relative risk for major adverse cardiovascular event with vadadustat was higher outside the United States.

3. Region-specific analyses reflect differences in trial patient characteristics, hemoglobin targets, and access to health care services.

Background: Vadadustat's global clinical program was comprised of four noninferiority trials comparing vadadustat and darbepoetin alfa for CKD-related anemia: two in dialysis-dependent CKD (DD-CKD) and two in non–dialysis-dependent CKD (NDD-CKD). Although vadadustat met prespecified noninferiority criteria for hematologic efficacy globally, it did not meet noninferiority criteria for cardiovascular safety in the non–dialysis-dependent CKD trials. The trials considered regional differences in treatment practices, including hemoglobin targets within (10–11 g/dl) and outside the United States (10–12 g/dl).

Methods: To examine region-specific outcomes, we performed prespecified analyses for US and non-US patient subgroups from the vadadustat global program. The primary safety end point was first occurrence of major adverse cardiovascular event (MACE; death from any cause or nonfatal myocardial infarction or stroke). The primary efficacy end point was change in hemoglobin from baseline to average values during weeks 24–36.

Results: Four thousand eighty-four/7399 (55%) randomized patients were enrolled in the United States. In pooled analyses of all US patients, MACE risk was similar among vadadustat-treated and darbepoetin alfa–treated patients (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.90 to 1.17). HRs were similar for US patients with DD-CKD (HR, 1.00; 95% CI, 0.84 to 1.18) and NDD-CKD (HR, 1.06; 95% CI, 0.87 to 1.29). In pooled analyses of non-US patients, MACE risk was numerically higher among vadadustat-treated patients (HR, 1.12; 95% CI, 0.94 to 1.33); the higher risk was primarily attributed to the NDD-CKD subgroup (HR, 1.29; 95% CI, 1.03 to 1.60). In the non-US DD-CKD subgroup, MACE risk was similar among vadadustat-treated and darbepoetin alfa–treated patients (HR, 0.88; 95% CI, 0.67 to 1.17). Changes in hemoglobin were similar among treatment groups in all regions, as were rates of treatment-emergent and serious adverse events.

Conclusions: In patients with DD-CKD, safety (vis-à-vis MACE) and efficacy (vis-à-vis change in hemoglobin) of vadadustat and darbepoetin alfa were similar when stratified by region (US versus non-US). In US patients with NDD-CKD, safety and efficacy of vadadustat and darbepoetin alfa were similar.

Clinical Trial registry name and registration number:: NCT02865850, NCT02892149, NCT02648347, NCT02680574.

Keywords: CKD; ESKD; anemia; cardiovascular events; clinical trial.