Safety of HIF prolyl hydroxylase inhibitors for anemia in dialysis patients: a systematic review and network meta-analysis

Abstract

Aim: We performed a systematic review and network meta-analysis evaluating the safety and efficacy of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) among dialysis chronic kidney disease patients.Methods: Safety was evaluated with any adverse events (AEs), serious adverse events (SAEs), and 12 common events. Efficacy was mainly analyzed with hemoglobin response. All reported results were summarized using mean difference and risk ratio (RR) with 95% confidence interval (CI). Publication bias was assessed through funnel plots.Results: Twenty trials (19 studies) with 14,947 participants were included, comparing six HIF-PHIs with erythropoiesis-stimulating agents (ESAs). No significant differences were indicated in overall AEs and SAEs between each HIF-PHI and ESA. The occurrence of gastrointestinal disorder was higher in enarodustat and roxadustat than in ESAs (RR: 6.92, 95% CI: 1.52–31.40, p = 0.01; RR: 1.30, 95% CI: 1.04–1.61, p = 0.02). The occurrence of hypertension was lower in vadadustat than in ESAs (RR: 0.81, 95% CI: 0.69–0.96, p = 0.01). The occurrence of vascular-access complications was higher in roxadustat (RR: 1.15, 95% CI: 1.04–1.27, p<0.01) and lower in daprodustat (RR: 0.78, 95% CI: 0.66–0.92, p<0.01) than in ESAs. In the risk of the other nine events, including cardiovascular events, no significant differences were observed between HIF-PHIs and ESAs. For hemoglobin response, network meta-analysis showed that compared with ESAs, significant increases were shown in roxadustat (RR: 1.04, 95% CI: 1.01–1.07, p<0.01) and desidustat (RR: 1.22, 95% CI: 1.01–1.48, p = 0.04), whereas noticeable reductions were indicated in vadadustat (RR: 0.88, 95% CI: 0.82–0.94, p<0.01) and molidustat (RR: 0.83, 95% CI: 0.70–0.98, p = 0.02). There was no significant difference between daprodustat and ESAs (RR: 0.97, 95% CI: 0.89–1.06, p = 0.47).Conclusion: Although HIF-PHIs did not show significant differences from ESAs in terms of overall AEs and SAEs, statistical differences in gastrointestinal disorder, hypertension, and vascular-access complications were observed between HIF-PHIs, which deserved to be noted in clinical decision making.Systematic review registration: This study is registered with PROSPERO (registration number CRD42022312252)

Consensus commentary and position of the Italian Society of Nephrology on KDIGO controversies conference on novel anemia therapies in chronic kidney disease

“…In contrast, in the ESA-controlled trials involving the DD-CKD population, the general consensus was that HIF-PHIs met non-inferiority criteria for MACE in cardiovascular outcome trials, in both incident and prevalent dialysis patients. The meta-analyses available after the KDIGO Conference confirmed the lack of increased risk of MACE with HIF-PHIs [ 6 , 7 , 9 , 11 – 14 ] (Table 1 ). Similarly, pooled analyses of roxadustat studies and vadadustat trials did not highlight any increased risk in MACE and mortality [ 16 , 17 ].…”

“…Six meta-analyses of HIF-PHI trials reported a significant reduction of hepcidin and ferritin levels and an increase of total iron binding capacity in patients receiving HIF-PHIs, consistent with their mechanism of action [ 6 – 9 , 11 , 14 ]; changes in serum iron and transferrin saturation were less predictable (Table 1 ). These effects translate into lower intravenous iron dosing with HIF-PHIs but the degree of this iron sparing effect is too small to be considered clinically meaningful [ 7 ].…”

“… Hypertension . Randomized controlled trials and recent meta-analyses did not evidence an increased risk of hypertension with HIF-PHIs in comparison with ESAs [ 6 , 8 , 9 , 11 , 13 , 14 ] (Table 1 ). Kidney disease progression .…”

“…However, because of their study design, these RCTs cannot demonstrate superiority versus the standard of care [5]. In this regard, some recent metaanalyses (Table 1), not discussed by KDIGO Conference participants because they were published after the Conference, reported a larger increase of hemoglobin levels in patients receiving HIF-PHIs [6][7][8][9][10][11]14], while hemoglobin target achievement did not differ [7,12].…”

“…In this regard, accumulating evidence published in the last three years (following the KDIGO conference) may shed some more light on the efficacy and safety of these new drugs. In particular, new findings emerging from several meta-analyses [6][7][8][9][10][11][12][13][14], one trial in peritoneal dialysis patients [15] and some post-hoc and pooled analyses of randomized controlled trials (RCTs) [16][17][18][19] might be helpful for better placement of HIF-PHIs in the clinical practice.…”