Supplementary Material for: Comparative Effectiveness and Safety of Roxadustat versus Erythropoiesis-Stimulating Agents in Patients Receiving Maintenance Hemodialysis: A Real-World Cohort Study

Introduction
Renal anemia, a common complication of chronic kidney disease (CKD), is traditionally managed with erythropoiesis-stimulating agents (ESAs), which carry cardiovascular risks. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), offers a novel mechanism by enhancing erythropoietin production and iron metabolism. While randomized controlled trials (RCTs) demonstrate its efficacy, real-world data (RWD) on long-term safety and effectiveness remain limited.

Methods
This retrospective study analyzed 6,414 hemodialysis patients with renal anemia from a single center (December 2018–December 2023), comparing roxadustat (n=3,184) and ESA (n=3,230) groups. Propensity score matching was used to balance the baseline characteristics. Efficacy outcomes included hemoglobin (Hb) changes (baseline to months 6–12 and 18–30) and Hb response rates. Safety endpoints assessed major adverse cardiovascular events (MACE), heart failure hospitalization (HHF), thromboembolism, and all-cause mortality. Sensitivity analyses addressed treatment crossover and confounding.

Results
Roxadustat showed significantly greater Hb increases versus ESA at 6–12 months (LSM difference: 0.46 g/dL, p=0.04) and 18–30 months (0.26 g/dL, p=0.01). Hb response rates were higher with roxadustat (84.0% vs. 76%, p<0.01). No significant differences were observed in MACE (HR 1.08, p=0.12), HHF (HR 0.88, p=0.25), thromboembolism (HR 1.05, p=0.34), or mortality (HR 0.94, p=0.29). Subgroup analyses suggested that roxadustat elevated MACE risk in patients with baseline hypertension or cardiovascular history, but sensitivity analyses nullified this association.

Conclusion
Roxadustat demonstrated superior efficacy in elevating and sustaining Hb levels compared to ESA over a longer observation period, with comparable cardiovascular safety in hemodialysis-dependent CKD patients. Roxadustat represents a viable alternative to ESA for renal anemia management, though long-term multicenter studies are needed to validate safety and optimize clinical use.