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Safe and Effective Treatment for Anemic Patients With Chronic Kidney Disease: An Updated Systematic Review and Meta-Analysis on Roxadustat.

ABSTRACT: Background: Roxadustat is a new oral drug for anemia in chronic kidney disease (CKD). This study aimed to synthesize the evidence from randomized controlled trial (RCT)-based studies that estimated the efficacy and safety of roxadustat in anemia patients with non-dialysis-dependent (NDD) and dialysis-dependent (DD) CKD. Methods: We searched the PubMed, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for related published studies. Moreover, we manually searched relevant pharmaceutical company websites and two international clinical trial registers to search for published and unpublished RCTs comparing roxadustat with erythropoietin-stimulating agents (ESAs) or placebo. Results: Fifteen RCTs (seven for DD-CKD patients, eight for NDD-CKD patients) were included in the meta-analysis, with 10,189 patients, 4,810 DD-CKD patients, and 5,379 NDD-CKD patients enrolled. Compared with ESAs (epoetin alfa or darbepoetin alfa) and placebo, roxadustat raised the hemoglobin level [weighted mean difference (WMD): 0.82 g/dL; 95% confidence interval (CI): 0.43-1.21], transferrin level (WMD: 0.5 g/L; 95% CI: 0.34-0.65), and TIBC level (WMD: 41.79 μg/dL; 95% CI: 38.67-44.92) and lowered the hepcidin level (WMD: -37.38 ng/ml; 95% CI: -46.63- -28.12) in both the DD-CKD and NDD-CKD patients with renal anemia. Roxadustat improved hemoglobin response and lowered the ferritin and TAST levels in the NDD-CKD patients but not in the DD-CKD patients. Furthermore, there was no difference between the treatment-emergent adverse events (TEAEs) of roxadustat and that of ESAs or placebo. But the incidence of serious TEAEs in the roxadustat group was significantly higher with NDD-CKD patients (OR: 1.15; 95% CI: 1.02-1.29). Conclusion: This study confirmed that roxadustat therapy could alleviate the anemia of DD-CKD and NDD-CKD patients by raising the hemoglobin level and regulating iron metabolism, but increased serious incidences of treatment-emergent adverse events (TEAEs) in NDD-CKD patients.

SUBMITTER: Tang M

PROVIDER: S-EPMC8283176 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAnemia is a common complication in chronic kidney disease (CKD) with increased morbidity and mortality. Recently published RCTs were conducted to compare the effect of the new medication roxadustat (ROX) with erythropoiesis-stimulating agent (ESA) in dialysis-dependent CKD (DD-CKD) patients. Our article aimed to meta-analyze published RCTs to investigate the efficacy and safety of ROX for anemia in DD-CKD patients and update the effect of the new studies on overall analysis with subsequent impact on management.MethodsElectronic databases (PubMed, EMBASE, Scopus, Web of Science, Cochrane Central, and Google Scholar) were searched systematically from inception to July 2021 by using this search term (Roxadustat OR ASP1517 OR FG4592 OR "FG-4592") AND (kidney OR renal) AND (Anemia). We only included randomized control trials (RCTs) that reported the primary outcome of change in hemoglobin (Hb) level and iron utilization parameters, including ferritin, serum iron, TSAT, TIBC, transferrin, and hepcidin.ResultsTen RCTs were finally included with 3031 patients in the ROX group and 2737 patients in the control group. ROX was associated with increase in Hb level (SMD: 0.2; 95% CI: 0.02, 0.39; P=0.03), TIBC (SMD: 0.79; 95% CI: 0.61, 0.98; P<0.00001), serum iron (SMD: 0.27; 95% CI: 0.18, 0.36; P<0.00001), transferrin (SMD: 0.98; 95% CI: 0.81, 1.15; P<0.00001) and decrease in hepcidin (SMD: -15.53; 95% CI: -28.07, -3.00; P<0.02) when compared with control group. There was no difference between ROX and the control group regarding ferritin level and TSAT. Sensitivity analysis by removing the most recent studies, Chen et al. or Hou et al. did not show significant difference in regard to change in Hb level. There was no difference between both groups regarding the serious side effects. However, ROX showed higher TEAEs when compared to the control group (RR: 1.03; 95% CI: 1.01, 1.05; P=0.002).DiscussionOur updated meta-analysis concluded that ROX increased Hb level and improved iron utilization parameters in DD-CKD patients, but ROX was associated with higher TEAEs. Our results support the use of ROX for DD-CKD patients with anemia. However, higher-quality RCTs are still needed to confirm the results of our review.

Project description:Background: Many studies demonstrated that roxadustat (FG-4592) could increase hemoglobin (Hb) levels effectively in anemia patients with chronic kidney disease (CKD). However, its safety remains controversial. This study aims to explore the risk of infection for CKD patients treated with roxadustat, especially focused on sepsis. Methods: We thoroughly searched for the randomized controlled trials (RCTs) comparing treatment with roxadustat versus erythropoiesis stimulating agents (ESAs) or placebo in PubMed, Embase, Cochrane Library, ClinicalTrials.gov, European Union Clinical Trials Register. Both on and not on dialysis anemia patients with CKD were included. Primary outcomes contained the incidence rates of sepsis. Secondary outcomes included infection-related consequences (septic shock and other infection events), general safety outcomes [all-cause mortality, treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)] and iron parameters. Moreover, a trial sequential analysis (TSA) was conducted to assess if the results were supposed to be a robust conclusion. Results: Eighteen RCTs (n = 11,305) were included. Overall, the incidence of sepsis (RR: 2.42, 95% CI [1.50, 3.89], p = 0.0003) and cellulitis (RR: 2.07, 95% CI [1.24, 3.44], p = 0.005) were increased in the roxadustat group compared with placebo group. In non-dialysis-dependent (NDD) CKD patients, the incidence of cellulitis (RR 2.01, 95% CI [1.23, 3.28], p = 0.005) was significantly higher in roxadustat group than that in the ESAs or placebo group. Both groups showed similar results in the incidence of septic shock (RR 1.29, 95% CI [0.86, 1.94], p = 0.22). A significant increased risk of all-cause mortality [risk ratios (RR): 1.15, 95% confidence interval (CI) [1.05, 1.26], p = 0.002] was found in roxadustat treatment, and TSA confirmed the result. Compared with ESAs or placebo, both the incident rates of TEAEs (RR:1.03, 95% CI [1.01, 1.04], p = 0.008) and TESAEs (RR: 1.06, 95% CI [1.02, 1.11], p = 0.002) were significantly increased in roxadustat group. As for iron parameters, changes from baseline (Δ) of hepcidin (MD: -26.46, 95% CI [-39.83, -13.09], p = 0.0001), Δ ferritin and Δ TSAT were remarkably lower in the roxadustat group, while Δ Hb, Δ iron and Δ TIBC increased significantly versus those in ESAs or placebo group. Conclusion: We found evidence that incidence rates of sepsis and cellulitis are higher in roxadustat group compared with placebo. This may be the result of improved iron homeostasis. The risk of all-cause mortality, TEAEs and TESAEs in CKD patients also increased in patients treated with roxadustat. We need more clinical and mechanistic studies to confirm whether roxadustat really causes infection.

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Safe and Effective Treatment for Anemic Patients With Chronic Kidney Disease: An Updated Systematic Review and Meta-Analysis on Roxadustat.

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