Efficacy and safety of HIF prolyl-hydroxylase inhibitor vs epoetin and darbepoetin for anemia in chronic kidney disease patients not undergoing dialysis: A network meta-analysis

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of oral medicines being developed for the treatment of anemia in chronic kidney disease (CKD) patients. This study aimed to compare the efficacy and safety of HIF-PHI vs epoetin and darbepoetin in CKD patients with anemia not undergoing dialysis. The PubMed, Embase, Cochrane Library, Web of Science, and clinicaltrials.gov databases were searched from inception to October 2019 for randomized controlled trials investigating different agents (six HIF-PHIs, epoetin, darbepoetin, and placebo) for treating CKD patients with anemia that did not undergo dialysis. The outcomes included a change in hemoglobin (Hb) levels and all-cause mortality. A total of 19 studies were included. Compared with the placebo, except for vadadustat (mean differences: 1.12, 95 % confidence interval [CI]: ‒0.11–2.35), the other drugs significantly increased Hb levels, with mean differences of 2.46 (95 % CI: 0.93–3.99) for desidustat, 1.81 (0.87–2.75) for enarodustat, 1.68 (0.64–2.72) for molidustat, 1.66 (0.89–2.44) for epoetin, 1.63 (0.69–2.56) for darbepoetin, 1.61 (0.99–2.22) for roxadustat, and 1.55 (0.74–2.36) for daprodustat. No differences were found in the Hb level elevations among these eight drugs. Compared with the placebo, there also was no significant association between the drugs and all-cause mortality (molidustat of RR, 0.39 [95 % CI, 0.06–2.59]; roxadustat, 0.40 (0.06–2.84); enarodustat, 0.33 (0.01–16.25); desidustat, 0.34 (0.01–17.00); epoetin, 0.50 (0.18–1.42); daprodustat, 0.54 (0.09–3.31); darbepoetin, 1.03 (0.65–1.65); and vadadustat, 1.43 (0.15–13.27)). No differences were observed in the all-cause mortality among the drugs. In conclusion, these HIF-PHIs are effective and relatively tolerant for treating anemia patients with CKD not undergoing dialysis. Further research should consider the limitations of our study to evaluate the value of these HIF-PHIs in clinical settings.