Rationale & ObjectiveIn the PRO2TECT trials, vadadustat was found to be noninferior to darbepoetin alfa in hematologic efficacy but not for major adverse cardiovascular events (MACE; all-cause death or nonfatal myocardial infarction or stroke) in patients with non–dialysis-dependent chronic kidney disease (NDD-CKD). We investigated the regional differences in MACE in the PRO2TECT trials.Study DesignPhase 3, global, open-label, randomized, active-controlled clinical trial.Setting & ParticipantsA total of 1,725 erythropoiesis-stimulating agent (ESA)-treated patients with anemia and NDD-CKD.Intervention1:1 randomization to receive vadadustat or darbepoetin alfa.OutcomesThe primary safety end point was the time to first MACE.ResultsAt baseline, patients in Europe (n=444) were primarily treated with darbepoetin alfa, showed higher proportions on low ESA doses (<90 U/kg/wk epoetin alfa equivalents) with a hemoglobin concentration of ≥10 g/dL compared with patients in the US (n=665) and non-US/non-Europe (n=614) regions. The MACE rates per 100 person-years in the 3 vadadustat groups across regions were 14.5 in the US, 11.6 in Europe, and 10.0 in the non-US/non-Europe groups, whereas event rates in the darbepoetin alfa group were considerably lower in Europe than in the US and non-US/non-Europe groups (6.7 vs 13.3 and 10.5, respectively). The overall hazard ratio for MACE for vadadustat vs darbepoetin alpha was 1.16; 95% CI, 0.93-1.45, but varied by geographical region, with a greater hazard ratio seen in Europe (US, 1.07; 95% CI, 0.78-1.46; Europe, 2.05; 95% CI, 1.24-3.39; non-US/non-Europe, 0.91; 95% CI, 0.60-1.37); interaction between study treatment and geographical region,P= 0.07). In Europe, ESA rescue was associated with a higher risk of MACE in both groups.LimitationsSeveral analyses are exploratory.ConclusionsIn this trial, there was a low risk of MACE in the darbepoetin alfa group in Europe. Patients in Europe were generally on low doses of ESA, with hemoglobin already within target range. The low risk of MACE may have been related to a limited need to switch and titrate darbepoetin alfa compared with the non-US/non-Europe group.FundingAkebia Therapeutics, Inc.Trial RegistrationClinicalTrials.gov identifier: NCT02680574