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. Hypoxia‐inducible factor prolyl hydroxylase inhibitors (HIF‐PHIs) are newer medicines used to treat anemia in people with chronic kidney disease. However, concerns have been raised that these medicines might worsen heart failure, especially in patients with pre‐existing heart failure. To investigate this issue, we analyzed healthcare claims data from a large nationwide database in Japan. We compared patients with heart failure who started HIF‐PHIs with similar patients who started conventional anemia treatments called erythropoiesis‐stimulating agents (ESAs), evaluating hospitalizations for heart failure and related outcomes. Among more than 37 000 patients, we found that HIF‐PHIs were not associated with a higher risk of heart failure hospitalization compared with ESAs. Similar results were observed when examining emergency hospitalizations and other indicators of worsening heart failure, and additional analyses using different statistical approaches produced consistent findings. These results suggest that HIF‐PHIs do not appear to substantially increase the risk of worsening heart failure in routine clinical practice, providing important information for clinicians treating anemia in patients with chronic kidney disease and heart failure.