Chong Shan, Xie Qiufen, Ma Tiantian, Xiang Qian, Zhou Ying, Cui Yimin
Department of Pharmacy, Peking University First Hospital, Beijing, China.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Front Pharmacol. 2022 Sep 16;13:967532. doi: 10.3389/fphar.2022.967532. eCollection 2022.
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. 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. Eighteen RCTs ( = 11,305) were included. Overall, the incidence of sepsis (RR: 2.42, 95% CI [1.50, 3.89], = 0.0003) and cellulitis (RR: 2.07, 95% CI [1.24, 3.44], = 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], = 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], = 0.22). A significant increased risk of all-cause mortality [risk ratios (RR): 1.15, 95% confidence interval (CI) [1.05, 1.26], = 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], = 0.008) and TESAEs (RR: 1.06, 95% CI [1.02, 1.11], = 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], = 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. 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.
许多研究表明，罗沙司他（FG - 4592）可有效提高慢性肾脏病（CKD）贫血患者的血红蛋白（Hb）水平。然而，其安全性仍存在争议。本研究旨在探讨接受罗沙司他治疗的CKD患者的感染风险，尤其关注脓毒症。我们在PubMed、Embase、Cochrane图书馆、ClinicalTrials.gov、欧盟临床试验注册库中全面检索了比较罗沙司他与促红细胞生成素（ESAs）或安慰剂治疗的随机对照试验（RCTs）。纳入了正在接受透析和未接受透析的CKD贫血患者。主要结局包括脓毒症的发生率。次要结局包括感染相关后果（感染性休克和其他感染事件）、一般安全性结局[全因死亡率、治疗中出现的不良事件（TEAEs）和治疗中出现的严重不良事件（TESAEs）]以及铁参数。此外，进行了一项试验序贯分析（TSA）以评估结果是否应得出可靠结论。纳入了18项RCTs（n = 11305）。总体而言，与安慰剂组相比，罗沙司他组脓毒症的发生率（RR：2.42，95%CI[1.50，3.89]，P = 0.0003）和蜂窝织炎的发生率（RR：2.07，95%CI[1.24，3.44]，P = 0.005）有所增加。在非透析依赖（NDD）的CKD患者中，罗沙司他组蜂窝织炎的发生率（RR 2.01，95%CI[1.23，3.28]，P = 0.005）显著高于ESAs或安慰剂组。两组在感染性休克的发生率方面显示出相似的结果（RR 1.29，95%CI[0.86，1.94]，P = 0.22）。在罗沙司他治疗中发现全因死亡率的风险显著增加[风险比（RR）：1.15，95%置信区间（CI）[1.05，1.26]，P = 0.002]，TSA证实了该结果。与ESAs或安慰剂相比，罗沙司他组TEAEs（RR：1.03，95%CI[1.01，1.04]，P = 0.008）和TESAEs（RR：1.06，95%CI[1.02，1.11]，P = 0.002）的发生率均显著增加。至于铁参数，罗沙司他组中，铁调素的基线变化（Δ）（MD： - 26.46，95%CI[-39.83， - 13.09]，P = 0.0001）、Δ铁蛋白和Δ转铁蛋白饱和度显著低于ESAs或安慰剂组，而ΔHb、Δ铁和Δ总铁结合力（TIBC）与ESAs或安慰剂组相比显著增加。我们发现有证据表明，与安慰剂相比，罗沙司他组脓毒症和蜂窝织炎的发生率更高。这可能是铁稳态改善的结果。接受罗沙司他治疗的CKD患者全因死亡率、TEAEs和TESAEs的风险也增加。我们需要更多的临床和机制研究来证实罗沙司他是否真的会导致感染。
