Efficacy and safety of erythropoietin and erythropoiesis-stimulating agents in the management of anemia in patients with chronic kidney disease: a systematic review

Anemia is a highly prevalent and consequential complication of chronic kidney disease (CKD). While erythropoiesis-stimulating agents (ESAs) have been the cornerstone of treatment for decades, safety concerns regarding higher hemoglobin targets and the challenge of ESA hyporesponsiveness persist. This systematic review aimed to synthesize the current evidence on the efficacy and safety of various ESA formulations and Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors (HIF-PHIs) for managing anemia in CKD patients. A systematic literature search was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines across several databases. Twelve studies (5 randomized controlled trials, 7 observational studies) were included after screening. Two independent reviewers performed study selection, data extraction, and risk-of-bias assessment. The reviewed evidence confirmed the efficacy of all ESA types (epoetin alfa, epoetin beta, darbepoetin alfa) and the HIF-PHI roxadustat in correcting hemoglobin levels. Roxadustat was non-inferior to epoetin alfa and demonstrated potential superior efficacy in one real-world study. Key modifiable risk factors for ESA hyporesponsiveness were identified, including iron deficiency (low TSAT), inflammation (high ferritin), and malnutrition (low albumin). Targeting a higher hemoglobin level (≥11 g/dl) in hyporesponsive patients did not improve renal or cardiovascular outcomes. Beyond hematological correction, ESA therapy was associated with improved endothelial function and a reduction in left ventricular mass. Darbepoetin alfa, administered every 4 weeks, was found to be more cost-effective than continuous erythropoietin receptor activator. Therefore, ESAs and HIF-PHIs are effective for anemia correction across the CKD spectrum. The choice of agent should consider efficacy, safety, cost-effectiveness, and patient-specific factors to optimize outcomes.