Risk of Heart Failure Hospitalization Associated With Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors Versus Erythropoiesis-Stimulating Agents: A Nationwide Claims-Based Cohort Study.

PURPOSE: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are increasingly used to treat renal anemia in patients with chronic kidney disease (CKD). We evaluated the risk of heart failure associated with HIF-PHIs compared with erythropoiesis-stimulating agents (ESAs) in routine clinical practice. METHODS: We conducted a nationwide, retrospective, active-comparator cohort study using a Japanese claims database. We included adults with non-dialysis CKD and heart failure initiating HIF-PHIs or ESAs alongside diuretic therapy between August 2020 and March 2025. The primary outcome was heart failure hospitalization. Secondary outcomes included emergency heart failure hospitalization and hospitalization requiring intravenous diuretics. Baseline characteristics were balanced using inverse probability of treatment weighting (IPTW) based on propensity scores. Hazard ratios (HRs), 95% confidence intervals (CIs), and sensitivity analyses were evaluated in predefined subgroups using Cox proportional hazards models. RESULTS: The cohorts comprised 14 995 HIF-PHI and 22 889 ESA users with baseline characteristics well balanced after IPTW adjustment. Heart failure hospitalization incidence rates per 1000 person-years (PY) were 157.8 for HIF-PHIs and 177.0 for ESAs. HRs were 0.93 [95% CI 0.87-1.01] for heart failure hospitalization, 0.94 [95% CI 0.84-1.03] for emergency heart failure, and 0.87 [95% CI 0.81-0.94] for intravenous diuretic administration. Results were generally consistent across subgroup and sensitivity analyses. CONCLUSIONS: Although residual confounding cannot be excluded because of the observational study design, HIF-PHIs were not associated with evidence of an increased risk of heart failure hospitalization in patients with heart failure.