Efficacy and Safety of Daprodustat for Anemia Therapy in Chronic Kidney Disease Patients: A Systematic Review and Meta-Analysis

Abstract

Objective: Daprodustat is a novel oral agent in treating anemia of chronic kidney disease (CKD), and several clinical trials have been conducted to compare daprodustat with recombinant human erythropoietin (rhEPO) or placebo. Our systematic review aimed to investigate the efficacy and safety of daprodustat for anemia treatment in both dialysis-dependent (DD) and non-dialysis-dependent (NDD) patients.Methods: Six databases were searched for randomized controlled trials (RCTs) reporting daprodustat vs. rhEPO or placebo for anemia patients in CKD. The outcome indicators were focused on hemoglobin (Hb), ferritin, transferrin saturation (TSAT), total iron-binding capacity (TIBC), vascular endothelial growth factor (VEGF), and serious adverse events (SAEs).Results: Eight eligible studies with 1,516 participants were included. For both NDD and DD patients, changes in Hb levels from baseline were significantly higher in daprodustat group than that in the placebo (mean difference (MD) = 1.73, [95% confidence interval (CI), 0.34 to 3.12], p = 0.01; MD = 1.88, [95% CI, 0.68 to 3.09], p = 0.002; respectively), and there was no significant difference between daprodustat and rhEPO group (MD = 0.05, [95% CI, −0.49 to 0.59], p = 0.86; MD = 0.12, [95% CI, −0.28 to 0.52], p = 0.55; respectively). The indexes of iron metabolism were improved significantly in the daprodustat group compared to placebo- or rhEPO-treated patients, while there was no similar change in terms of TSAT for DD patients. Furthermore, no trend of increasing plasma VEGF was observed in daprodustat-treated subjects. As for safety, there was no significant difference in the incidence of SAEs between daprodustat and placebo treatment, while the incidence of SAEs in the daprodustat group was significantly lower than that in the rhEPO group.Conclusion: Daprodustat was efficacious and well tolerated for anemia in both NDD and DD patients in the short term based on current RCTs. And daprodustat may become an effective alternative for treatment of anemia with CKD. Since the application of daprodustat is still under exploration, future researches should consider the limitations of our study to evaluate the value of daprodustat.

Treatment of Anemia in Kidney Disease: Beyond Erythropoietin

“…There was no trend of increasing plasma vascular endothelial growth factor (VEGF) among daprodustat-treated subjects. 64 Despite its relatively short half-life (Table 1), a 29-day phase 2 study of daprodustat in 103 HD patients demonstrated efficacy of daprodustat when administered three-times weekly at approximately twice the daily dose. 65 In a phase 3 study in Japan, 271 HD patients were randomized to continue darbepoetin or conversion to daprodustat with 52-week follow-up.…”

“…82 Phase 3 clinical trials of sufficient duration and statistical robustness to assess MACE and other cardiovascular end-points may not be adequate to address some of these other potential complications of HIF stabilizer therapy which may be less frequent and take longer to manifest. With regards to angiogenesis, studies of vadadustat and daprodustat examined VEGF levels and reported no consistent increases; 34,64 data from phase 3 trials do not show acceleration of diabetic retinopathy; 66,83 and studies to date have not demonstrated any increase in malignancies. 84 Thrombotic events were increased in DD-CKD patients treated with roxadustat vs. epoetin 52 but similar findings have not been reported in other phase 3 studies of HIF stabilizers.…”

“…There was no trend of increasing plasma vascular endothelial growth factor among daprodustat-treated individuals. 64 Despite its relatively short half-life ( Table 1 ), a 29-day phase 2 study of daprodustat in 103 HD patients demonstrated efficacy of daprodustat when administered 3-times weekly at approximately twice the daily dose. 65 …”

Efficacy and Safety of Daprodustat Vs rhEPO for Anemia in Patients With Chronic Kidney Disease: A Meta-Analysis and Trial Sequential Analysis

“…Researchers have investigated the efficacy and safety of daprodustat in recent years. Although pervious meta-analyses ( Xie et al, 2018 ; Zheng et al, 2020a ) have shown that daprodustat could improve hemoglobin and is well tolerated in CKD patients, the evidence for its efficacy and safety in NDD patients and DD patients is still lacking. Therefore, we performed this meta-analysis and trial sequential analysis (TSA) to further evaluate the efficacy and safety of daprodustat for the treatment of CKD-associated anemia in both NDD and DD patients.…”

Efficacy of Different Doses of Daprodustat for Anemic Non-dialysis Patients with Chronic Kidney Disease: A Systematic Review and Network Meta-Analysis

“…A previous meta-analysis by Zheng et al pooled data comparing the effect of daprodustat and control in anemia in patients and found that daprodustat could maintain hemoglobin with lower adverse events than rhEPO. However, they neither separated data on dialysis and non-dialysis patients nor accounted for different doses of daprodustat [ 22 ]. In addition, the previous meta-analysis compared the direct estimates of effect for only two arms at a time, in contrast to network meta-analyses that compare the efficacy of study arms directly and indirectly with no previous network meta-analysis (NMA) synthesized evidence about the safety and efficacy of all available daprodustat doses for anemia of CKDs in non-dialysis patients.…”