Safety Profile of Roxadustat in Anemic Patients: A Meta-Analysis of 21 RCTs.

Objective: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor used to treat anemia in patients with chronic kidney disease. We aimed to assess its safety and tolerability profile through a meta-analysis of randomized controlled trials (RCTs). Methods: A systematic search of the Cochrane CENTRAL, Ovid Medline R, PubMed, and Web of Science databases was conducted up to January 1, 2025 was conducted. RCTs comparing roxadustat with control groups were included. Inverse-variance-weighted random-effects models were used. The primary outcome was the risk of any serious treatment-emergent adverse event (TEAE). Subgroup analyses were based on etiology, comparator, and prior erythropoiesis-stimulating agent (ESA) use. Results: Twenty-one RCTs involving 11.686 patients were included. Roxadustat was not associated with a higher risk of any serious TEAE compared with placebo [risk ratio (RR) =1.37, 95% confidence interval (CI): 0.79-2.37] or with ESA (RR=1.05, 95% CI: 0.99-1.10). Similarly, cardiac serious adverse events (SAEs) did not differ significantly when compared with ESA (RR=1.11, 95% CI: 0.75-1.12) or placebo (RR=1.11, 95% CI: 0.92-1.35). Hyperkalemia incidence was significantly higher compared with placebo (RR=1.25, 95% CI: 1.02-1.53) but not compared with ESA (RR=1.03, 95% CI: 0.77-1.36). There were also no significant differences in the incidence of serious infections (RR=0.74, 95% CI: 0.21-2.59), azotemia (RR=0.96, 95% CI: 0.46-2.00), hypertension (RR=1.06, 95% CI: 0.93-1.21), or pneumonia (RR=0.96, 95% CI: 0.81-1.14) compared with ESA. Notably, withdrawal due to adverse events (RR=2.11, 95% CI: 1.59-2.79) was significantly higher compared with ESA. TEAEs leading to death were similar compared with ESA (RR=0.98, 95% CI: 0.85-1.13) but were increased compared with placebo (RR=1.21, 95% CI: 1.04-1.42). All-cause mortality was significantly lower than with placebo (RR=0.40, 95% CI: 0.28-0.57) but was similar to ESA (RR=0.89, 95% CI: 0.57-1.37). Subgroup analyses for the primary outcome by etiology and prior ESA use were not consistent with the main findings. Conclusions: Roxadustat demonstrated a SAE profile generally comparable to that of ESA, with no significant differences in cardiac SAEs, serious infections, azotemia, hypertension, or pneumonia. Hyperkalemia was more frequent compared with placebo, and withdrawals due to adverse events were more frequent compared with ESA. TEAEs leading to death were similar to ESA but higher than with placebo, whereas all-cause mortality was lower than with placebo and comparable to ESA. Taken together, current evidence supports the overall non-inferiority of roxadustat to ESA in terms of safety.