Use of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Agents for Anemia in Non-Dialysis-Dependent Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Background: Anemia is a common complication associated with chronic kidney disease (CKD), driven by decreased erythropoietin (EPO) production and dysregulated iron metabolism. Anemia is associated with decreased quality of life, as well as increased cardiovascular events, dialysis requirements, and mortality. Treatment classically consists of iron repletion and erythropoietin stimulating agents (ESA). However, use of these agents can be associated with hyporesponsiveness, a need for close monitoring to avoid adverse cardiovascular events, and patient inconvenience due to subcutaneous or intravenous administration. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel oral therapeutic agents that promote accumulation of HIF transcription factors and expression of HIF-responsive genes, leading to increased synthesis of EPO and proteins involved in iron metabolism. Multiple large randomized controlled trials (RCTs) investigating the safety and efficacy of HIF-PHIs in the treatment of anemia of non-dialysis dependent CKD (NDD-CKD) have been completed. However, to the best of our knowledge, there have been no recent comprehensive systematic reviews synthesizing this evidence.

Aim: The objective of this systematic review is to assess the safety and efficacy of HIF-PHIs in the treatment of anemia caused by NDD-CKD.

Methods: A comprehensive search of MEDLINE, Embase, Cochrane (CENTRAL), and the grey literature was done from inception to April 2022. Studies were screened at abstract and full-text level independently and in duplicate. English-language phase three RCTs investigating the use of HIF-PHIs versus placebo or ESAs in anemia of NDD-CKD were included. Baseline characteristics, intervention details, comparator details, and outcome measurement timing were collected. Our primary efficacy outcome measures were mean change in hemoglobin from baseline and proportion of patients achieving a hemoglobin response. Our primary safety outcome was major adverse cardiac events (MACE) defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality. Meta-analysis was done using DerSimonian and Laird random effects model and reported as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CI).

Results: 14 studies with a total of 12,681 patients were included in the analysis. HIF-PHIs were associated with increased hemoglobin response rate compared to placebo (RR 9.02, 95%CI 6.85,11.86, p<0.005; I²=56%, N=5). There was no significant difference in hemoglobin response rate for HIF-PHIs versus ESAs (RR 0.97, 95%CI 0.9,1.04, p=0.36; I²=76%, N=9). HIF-PHIs were associated with an increased change in hemoglobin from baseline compared to placebo (MD=1.57, 95%CI 1.29,1.85, p<0.05; I²=93%, N=4). There was no significant difference in mean change in hemoglobin from baseline between HIF-PHIs and ESAs (MD -0.06, 95%CI -0.19,0.07, p=0.38; I²=0, N=2). There was no statistically significant difference in MACE between HIF-PHI and placebo (RR 1.14, 95%CI 0.93,1.40, p=0.2; I²=11%, N=4) or ESA (RR 1.03, 95%CI 0.89, 1.19, p=0.70; I²=23%, N=9).

Conclusion: HIF-PHIs are associated with increased mean change in hemoglobin and hemoglobin response rate compared to placebo. HIF-PHIs are non-inferior to ESAs for these outcomes. When used to current hemoglobin targets, MACE outcomes are similar to those seen with ESAs.

Crowther:ASH: Other: Treasurer; AstraZeneca: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Speakers Bureau; Hemostasis reference Laboratories: Consultancy; Pfizer: Speakers Bureau; Precision Biologics: Consultancy.