Safety of HIF Prolyl-Hydroxylase Inhibitors for Anemia in Dialysis Patients: A Systematic Review and Network Meta-Analysis

Abstract

Aim: We performed a systematic review and network meta-analysis, evaluating the safety and efficacy of Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) among dialysis chronic kidney disease (CKD) patients. Methods: Safety was evaluated with any adverse events (AEs), serious adverse events (SAEs), and twelve common events. Efficacy was mainly analyzed with hemoglobin (Hb) response. All reported results were summarized using mean difference (MD) and risk ratio (RR) with 95% confidence interval (CI). Publication bias was assessed through funnel plots. Results: Twenty trials with 14,947 participants were included, comparing six HIF-PHIs with Erythropoiesis-stimulating agents (ESAs). No significant differences were indicated in AEs and SAEs between each HIF-PHI and ESA. The occurrence of gastrointestinal disorder was higher in Enarodustat and Roxadustat than in ESAs (RR: 6.92, 95% CI: 1.52-31.40, p=0.01; RR: 1.30, 95% CI: 1.04-1.61, P=0.02). The occurrence of hypertension was lower in Vadadustat than in ESAs (RR: 0.81, 95% CI: 0.69-0.96, p=0.01). The occurrence of vascular-access complications was higher in Roxadustat (RR: 1.15, 95% CI: 1.04-1.27, p＜0.01) while lower in Daprodustat (RR: 0.78, 95% CI: 0.66-0.92, p＜0.01) than in ESAs. In the risk of the other nine events, including cardiovascular events, no significant differences were observed between HIF-PHIs and ESAs. For efficacy, network meta-analysis showed that the overall performance was similar to ESAs. Conclusion: Although HIF-PHIs did not show significant differences from ESAs in terms of overall AEs and SAEs, statistical differences in gastrointestinal disorder, hypertension, and vascular-access complications were observed between HIF-PHIs, which deserved to be noted in clinical decision-making.

Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets

“…In dialysis-dependent CKD anemia patients, there were no significant differences found in this network meta-analysis between HIF-PHIs and erythropoiesis-stimulating agents (ESAs) in terms of various risks (including cardiovascular events, hyperkalemia, cancer, hypotension, muscle spasms, and etc.). 516 However, for long-term HIF-PHI use, personalized and selective approaches are crucial, particularly for cancer patients with chemotherapy-related anemia. 6 Thus, competitive and selective PHD inhibitors are still being eagerly wanted.…”