Meta-analysis of HIF-PHIs versus ESAs or Placebo in CKD With Anemia

Individuals with chronic kidney disease (CKD) often experience anemia, a complication associated with increased incidence of cardiovascular disease, hospitalizations, and mortality. The current mainstays of treatment for anemia associated with CKD are erythropoiesis-stimulating agents (ESAs), typically epoetin and darbepoetin, in combination with iron supplementation.

ESAs decrease the need for blood transfusions; however, high-dose ESAs have been associated with increased risk for cardiovascular events, progression to kidney failure, and death. Due in part to concerns regarding the safety of ESAs, anemia may be untreated or delayed in patients with CKD stage 3b to 5 who are not receiving dialysis.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as potential alternative treatment for anemia in CKD. HIF-PHIs activate HIF transcription factors, leading to functional activation of early-response target genes encoding proteins such as erythropoietin and the erythropoietin receptor. Further, HIF-PHIs are administered orally and increase endogenous erythropoietin within or near the physiologic range while improving iron homeostasis.

Qiyan Zheng, MD, and colleagues conducted a systematic review and meta-analysis to assess the cardiac and renal adverse effects of HIF-PHIs among patients with CKD and anemia. Results were reported in the American Journal of Kidney Diseases.

The researchers searched PubMed, Embase, Web of Science, Cochrane Library database, and, to include randomized controlled trials that were completed but unpublished, the ClinicalTrials.gov website. The search timeframe was from time of database inception to March 2021, with no language restrictions applied.

Eligible studies were randomized controlled trials that met the following population, intervention, comparison outcomes, and study criteria: (1) study population consisting of non-dialysis dependent patients with CKD and anemia; (2) use of HIF-PHI; (3) placebo or ESA as comparator; and (4) primary outcomes of cardiac adverse events and kidney-related adverse events.

Cardiac adverse events included cardiovascular death, myocardial infarction, unstable angina pectoris, ischemic stroke, heart failure, arrhythmia, or other cardiac and valvular disease, or major adverse cardiovascular events. Kidney-related adverse events were worsening of CKD or decrease in estimated glomerular filtration rate (eGFR), kidney failure or initiation of dialysis, acute kidney injury, nephritis, azotemia, or renal disorders or kidney-related adverse events. Secondary outcomes searched for included the incidence of hypertension and hyperkalemia, the number of patients who progressed to kidney failure or started dialysis, severe adverse events, drug-related serious adverse events, and death.

The Mantel-Haenszel method was used to pool dichotomous variables, presented as risk ratios (RRs). Analyses of subgroups assessed varying interventions times and HIF-PHIs, as well as phase 2 versus phase 3 trials.

The initial search identified 13,384 articles. Of those, 3954 were duplicates, and 9430 titles and abstracts were then screened. Full-text screening included 112 articles, resulting in 23 eligible articles included in the analysis (15,144 participants). Most included trials were judged to have a low or unclear risk of bias for random sequence generation, allocation concealment, incomplete outcome data, selective reporting, and other bias. Ten were judged to be at high risk of bias for masking of participants and personnel, and 10 were judged to be at high risk of bias for masking of outcomes due to the open-label design of the studies.

Twenty trials representing 14,561 reported cardiac adverse events. In pooled results, there was no significant difference in the risk of cardiac adverse events seen in the HIF-PIH group compared with the placebo group (RR, 1.02; 95% CI, 0.89-1.16; I²=0%) or the ESA group (RR, 1.06; 95% CI, 0.98-1.14; I²=10%). In a sensitivity analysis that excluded three studies that did not report the total number of cardiac adverse events, there was no significant change in the overall effect size and heterogeneity.

The subgroup analysis of intervention time (<52 or ≥52 weeks) on outcomes demonstrated an association between the HIF-PHIs group and a significantly lower risk of cardiac adverse events in the short term (<52 weeks) compared with the placebo group. There was no statistically significant difference in the long term (≥52 weeks). There were no significant differences in additional subgroup analyses for each of the HIF-PHI drugs (roxadustat, daprodustat, vadadustat, and molidustat) and the trial phases (phase 2 and phase 3).

A total of 22 trials reported kidney-related adverse events (13,437 participants). In meta-analysis, there were no statistically significant differences in the risk of kidney-related adverse events seen in the HIF-PHIs group compared with the placebo group (RR, 1.09; 95% CI, 0.98-1.20; I²=0%) or the ESA group (RR, 1.00; 95% CI, 0.94-1.06; I²=0). In sensitivity analyses excluding eight studies that did not report the total number of kidney-related adverse events, there was no significant change in overall effect size and heterogeneity. There were no significant differences in the incidence of kidney-related adverse events in subgroup analysis of intervention times (<52 or ≥52 weeks), HIF-PHI drugs ((roxadustat, daprodustat, vadadustat, and molidustat), and the trial phases (phase 2 and phase 3).

Hypertension events were reported in 19 trials, with pooled results showing a higher risk of hypertension in the HIF-PHIs groups compared with the placebo group. When compared with ESA group, the risk of hypertension was lower in the HIF-PHIs group. Seventeen trials reported hyperkalemia, with pooled results showing a higher risk of hyperkalemia in the HIF-PHIs group compared with the placebo group. There was no significant difference in risk when compared with the ESA group.

The inconsistency in reporting criteria of cardiac and kidney-related adverse events and dosage of HIF-PHIs across trials was cited as a limitation to the study. Also cited as study limitation were not evaluating specific laboratory indicators related to cardiac and kidney function, and the inconsistency in dosage of HIF-PHIs in the included trials.

In summary, the researchers said, “According to the current evidence, HIF-PHIs did not significantly increase the risk of cardiac or kidney-related adverse events, kidney failure events, serious adverse events, or death in patients with anemia and CKD who are not receiving dialysis. HIF-PHIs were associated with an increased risk of hypertension and hyperkalemia compared with placebo, but they were associated with a lower risk of hypertension and a similar risk of hyperkalemia compared with ESA treatment. Further research should consider the limitations of our study to explore the impacts of cardiac and kidney-related adverse events of HIF-PHIs for anemia of CKD.”

Takeaway Points

1. Researchers reported results of a review and meta-analysis of the adverse effects on cardiac and renal outcomes in patients with nondialysis-dependent chronic kidney disease (CKD) and anemia receiving hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs).
2. Trials included in the analysis compared HIF-PHIs to placebo or to erythropoiesis-stimulating agents (ESA).
3. There were no statistically significant differences in the occurrence of cardiac- and kidney-related adverse events in the HIF-PHIs groups compared with placebo or ESA groups.

Source: American Journal of Kidney Diseases