Supplementary file 1_Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors on transfusion and intravenous iron use in chronic kidney disease anemia: a systematic review and meta-analysis.docx

Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. Furthermore, the certainty of evidence was assessed using the GRADE framework.</p>Results<p>A total of 36 independent randomized controlled trials involving 27,680 participants with CKD-associated anemia were included. The trials evaluated six HIF-PHIs, namely, roxadustat, daprodustat, vadadustat, molidustat, enarodustat, and desidustat, against placebo, standard treatment or care, or an ESA.

Compared with control interventions, HIF-PHIs significantly reduced the risk of any red blood cell transfusion (RR = 0.74, 95% CI: 0.58–0.93) and rescue red blood cell transfusion (RR = 0.70, 95% CI: 0.53–0.92). Intravenous iron outcomes generally favored HIF-PHIs, although neither the risk of any intravenous iron use (RR = 0.66, 95% CI: 0.38–1.14) nor the mean monthly intravenous iron dose (SMD = −0.19, 95% CI: −0.42 to 0.03) reached statistical significance, indicating residual uncertainty.

Rates of major adverse cardiovascular events, all-cause mortality, and serious adverse events were not significantly increased with HIF-PHIs.</p>Conclusion<p>In patients with CKD-associated anemia, HIF-PHIs improved hemoglobin without significantly increasing major adverse cardiovascular events, all-cause mortality, or serious adverse events; however, the small increase in any adverse event and the hyperkalemia signal in non-dialysis-dependent patients warrant attention.

Together with the significant reduction in red blood cell transfusion and the possible reduction in intravenous iron use, these findings support HIF-PHIs as a promising oral treatment option. Longer follow-up and continued post-marketing surveillance are required to clarify long-term safety and effects across patient subgroups.</p>Systematic Review Registration<p>crd.york.ac.uk/PROSPERO/view/CRD420261387833, Identifier CRD420261387833.</p>