Cardiac and Kidney Adverse Effects of HIF Prolyl-Hydroxylase Inhibitors for Anemia in Patients With CKD Not Receiving Dialysis: A Systematic Review and Meta-analysis

Zheng, Qingyin; Wang, Yahui; Yang, Huisheng; Sun, Luying; Zhang, Pingna; Zhang, Xueqin; Guo, Jing; Liu, Yu Ning; Liu, Wei Jing

doi:10.1053/j.ajkd.2022.09.014

Cited by 13 publications

(17 citation statements)

References 56 publications

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“…On the other hand, our findings have important implications for understanding the clinical expression when categorizing sFas as a possible marker or even if it is a possible uremic retention solute and, thus, might contribute to the development of new studies that focus on pathophysiological processes, and possibly, the treatment of anemia in patients with CKD, as with newer ESA drugs [49][50][51].…”

Section: Plos Onementioning

confidence: 87%

A retrospective view of the relationship of soluble Fas with anemia and outcomes in chronic kidney disease

et al. 2023

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Background Anemia is common in chronic kidney disease (CKD) and is associated with outcomes. In addition, serum soluble Fas (sFas) levels are related to anemia and erythropoietin (EPO) resistance. Objectives Firstly, to compare clinical data and serum levels of sFas, EPO, and pro-inflammatory markers between patients with non-dialytic CKD (NDD-CKD) and healthy subjects. Subsequently, to compare and evaluate the relationship of serum EPO, sFas levels with anemia, and outcomes in patients with NDD-CKD over a long follow-up period. Methods We performed a retrospective study in 58 NDD-CKD patients compared with 20 healthy subjects on complete blood count, kidney function, serum EPO, sFas, and inflammatory markers (CRP, IL- 6, and IFN-γ) at baseline. We then compared the same baseline data between patients with NDD-CKD who evolved to anemia and those who did not have anemia over the follow-up. We also evaluated the frequency of outcomes in patients with CKD with higher sFas levels. Finally, we performed a multivariate analysis of factors associated with CKD anemia. Results There were lower eGFR and Hb but higher serum inflammatory markers, sFas levels, sFas/eGFR, and EPO/Hb ratios in patients with NDD-CKD. Comparatively, on the other hand, NDD-CKD patients with anemia had lower eGFR but were older, had more diabetes, and had higher sFas/ eGFR, EPO/Hb ratios, and serum levels of IL-6 and sFas than NDD-CKD without anemia for an extended period. In addition, there was an association in a multivariate analysis of diabetes, age, and sFas levels with kidney anemia. Furthermore, there were higher frequencies of outcomes in increased serum sFas levels. Conclusion As an elective risk factor, serum sFas levels, in addition to age and diabetes, were independently associated with kidney anemia for an extended period. Thus, more studies are necessary to analyze the proper relationship of sFas with kidney anemia and its outcomes and therapy in CKD.

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Section: Plos Onementioning

confidence: 87%

A retrospective view of the relationship of soluble Fas with anemia and outcomes in chronic kidney disease

et al. 2023

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“…Similar findings were reported by Takkavatakarn et al ., including unpublished data also [ 20 ]. In another meta-analysis limited to non-dialysis CKD patients, the risk of cardiac disorders was evaluated in 20 studies with 14 561 individuals, including 11 placebo-controlled trials [ 19 ]. When considering RCTs with ESA as comparator (nine studies with 9470 participants), as in the present meta-analysis, the authors found no difference in the cardiovascular risk between the HIF-PHIs and ESA arms [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…In another meta-analysis limited to non-dialysis CKD patients, the risk of cardiac disorders was evaluated in 20 studies with 14 561 individuals, including 11 placebo-controlled trials [ 19 ]. When considering RCTs with ESA as comparator (nine studies with 9470 participants), as in the present meta-analysis, the authors found no difference in the cardiovascular risk between the HIF-PHIs and ESA arms [ 19 ]. Therefore, based on our and previous findings, it is possible to exclude an evident cardiovascular safety signal in patients using HIF-PHIs.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with chronic kidney disease: meta-analysis of phase 3 randomized controlled trials

Minutolo

Liberti

Simeon

et al. 2023

Clinical Kidney Journal

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Background Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new therapeutic agents for anaemia of chronic kidney disease (CKD). We evaluated by metanalysis and meta-regression efficacy and safety of HIF-PHIs in patients with CKD-related anaemia. Methods We selected phase-3 randomized clinical trials (RCTs) comparing HIF-PHIs and erythropoiesis stimulating agents (ESAs) in dialysis and non-dialysis patients. Efficacy outcomes were the changes from baseline of haemoglobin, iron parameters (hepcidin, serum iron, TIBC, TSAT, ferritin,) and intravenous iron dose; as safety outcomes we considered cancer, adjudicated major adverse cardiovascular events (MACE), MACE+ (MACE plus hospitalization for hearth failure or unstable angina or thromboembolic event), thrombotic events (deep vein thrombosis, pulmonary embolism), artero-venous fistula (AVF) thrombosis, and death. Results We included 26 RCTs with 24,387 patients. Random effect meta-analysis of unstandardized mean difference between HIF-PHIs and ESAs showed a significant change in haemoglobin levels from baseline of 0.10 g/dL (95%CI, 0.02-0.17). Meta-regression analysis showed significantly higher haemoglobin change for HIF-PHIs in younger patients and versus short-acting ESA (0.21 g/dL, 95%CI, 0.12-0.29 versus -0.01, 95%CI, -0.09-0.07 in studies using long-acting ESA, P<0.001). No significant effect on heterogeneity was found for type of HIF-PHIs. In comparison with ESAs, HIF-PHIs induced a significant decline in hepcidin and ferritin and a significant increase in serum iron and TIBC, while TSAT did not change; intravenous iron dose was lower with HIF-PHI (-3.1 mg/week, 95%CI -5.6 to -0.6, P = 0.020). Rate ratio of cancer (0.93, 95%CI: 0.76-1.13), MACE (1.00, 95%CI: 0.94-1.07), MACE+ (1.01, 95%CI: 0.95-1.06), thrombotic events (1.08, 95%CI: 0.84-1.38), AVF thrombosis (1.02, 95%CI: 0.93-1.13) and death (1.02, 95%CI: 0.95-1.13) did not differ between HIF-PHIs and ESAs. Conclusions HIF-PHIs at the doses selected for the comparisons are effective in correcting anaemia in comparison with ESA therapy with a significant impact on iron metabolism without notable difference among various agents. No safety signals emerge with use of HIF-PHIs.

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“…Another meta-analysis of seven trials including 7,933 patients indicated that daprodustat might have a better impact on dialysis-dependent patients in optimizing iron metabolism despite being non-inferior in improving anemia in both DD and non-dialysis-dependent (NDD) patients ( Fu et al, 2022 ). While a meta-analysis that included 14 studies indicated that DD patients using HIF-PHIs had a higher risk of serious adverse reactions compared to those using EPO ( Wu et al, 2022 ), a new meta-analysis containing 23 studies showed a significant difference in the risk of cardiac and kidney-related AEs in NDD patients ( Zheng et al, 2023 ), while there is still a lack of direct comparison between HIF-PHIs, which restricts the clinical application of these agents in DD patients. Therefore, to provide evidence for their safety in clinical application, we conducted a systematic review and network meta-analysis of RCTs comparing HIF-PHIs versus ESAs, to summarize their pairwise comparison and overall safety and efficacy.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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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)

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Cardiac and Kidney Adverse Effects of HIF Prolyl-Hydroxylase Inhibitors for Anemia in Patients With CKD Not Receiving Dialysis: A Systematic Review and Meta-analysis

Cited by 13 publications

References 56 publications

A retrospective view of the relationship of soluble Fas with anemia and outcomes in chronic kidney disease

A retrospective view of the relationship of soluble Fas with anemia and outcomes in chronic kidney disease

Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with chronic kidney disease: meta-analysis of phase 3 randomized controlled trials

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

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