Association of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors with Cardiovascular Events and Death in Dialysis Patients: A Systematic Review and Meta-Analysis

Background: Anemia is a common finding among patients with advanced chronic kidney disease, especially those on dialysis. The recent introduction of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) has raised some concerns about the cardiovascular and thrombotic complications of this class of drugs. Objectives: This meta-analysis aimed to assess the safety of HIF-PHIs in patients with end-stage kidney disease (ESKD) versus standard therapy with erythropoiesis-stimulating agents (ESAs). Methods: Databases were searched on April 2022. Studies that reported incidence of all-cause mortality; major cardiovascular adverse events (MACEs); myocardial infarction (MI); stroke and thrombotic events in the use of HIF-PHIs or ESA on ESKD patients in hemodialysis or peritoneal dialysis were evaluated. Data were extracted from published reports, and quality assessment was performed per Cochrane recommendations. Results: 12,821 patients from ten randomized controlled trials were included in this study. Most patients (83%) were on hemodialysis. 6,461 (50.3%) were using HIF-PHIs, and 6,360 (49.6%) were in the ESA group. The pooled estimated incidence of all-cause mortality was 769 in the HIF-PHIs group (relative-risk ratios (RR): 1.04; confidence interval (CI): 0.95-1.14; p = 0.52; I-2 = 0%). There was no difference in the groups regarding the outcomes of MACE in the analysis of the three studies that reported this outcome (RR: 0.95; CI: 0.87-1.04; p = 0.69; I-2 = 0%). In addition, there was no statistical difference among the outcomes of MI, stroke, or thrombotic events. Conclusions: Among patients with ESKD on dialysis, the use of HIF-PHIs was non-inferior regarding the safety outcomes when compared to standard of care therapy.