Abstract
The aim of this systematic review and network meta‐analysis was to clarify the risk of acute kidney injury (AKI) and acute heart failure associated with hypoxia‐inducible factor–prolyl hydroxylase inhibitors (HIF‐PHIs) in patients with anemia of chronic kidney disease. The certainty of evidence for each outcome was assessed using the Confidence in Network Meta‐Analysis approach. The primary outcomes were AKI and acute heart failure, while the secondary outcome was any kidney injury. Thirty‐five studies, performed between 2009 and 2025, were included in the network meta‐analysis. HIF‐PHIs were associated with a higher risk of AKI compared with erythropoiesis‐stimulating agents (ESAs) (risk ratio [RR] 1.23, 95% confidence interval [CI] 1.02–1.47, moderate certainty) and placebo (RR 1.40, 95% CI 1.11–1.75, high certainty). HIF‐PHIs were also associated with an increased risk of any kidney injury compared with placebo (RR 1.13, 95% CI 1.01–1.26, moderate certainty). ESAs ranked lower in terms of acute heart failure risk than both HIF‐PHIs and placebo, although the differences were not statistically significant. Vadadustat (RR 0.30, 95% CI 0.12–0.74, moderate certainty) and ESAs (RR 0.40, 95% CI 0.17–0.94, high certainty) were associated with a lower risk of acute heart failure compared with placebo. In conclusion, HIF‐PHIs may be associated with an increased incidence of AKI compared with placebo and ESAs. In contrast, vadadustat and ESAs might be associated with a decreased incidence of acute heart failure compared with placebo. Further robust studies should be conducted to validate these findings.