INTRODUCTION
The global prevalence of chronic kidney disease (CKD) is approximately 9.1%, affecting about 700 million people[1]. Anemia, a common complication of CKD related to the heightened risk of cardiovascular events, increased red blood cell transfusion, and decreased health-related quality of life[2]. Erythropoiesis-stimulating agents (ESAs) (particularly epoetin and darbepoetin) and iron supplements have become the mainstays of treatment, avoiding the risk of blood transfusions while ensuring optimal hemoglobin target levels[3, 4]. Nevertheless, studies have shown that high-dose ESAs are relevant to increased risks of cardiovascular events and infection[5], as well as hospitalizations and mortality[6]. The FDA has also revisited the prescribing information with black-box warnings for epoetin alfa and darbepoetin alfa; patients are at greater risk of adverse outcomes when the hemoglobin target value is >11g/dl[7, 8].
Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), an orally active, small-molecule, is a new drug type prepared for anemic CKD patients[9]. To promote erythropoiesis in the kidney and liver, HIF-PHI can emulate the natural reaction to hypoxia [10-12], and thus stimulate endogenous erythropoiesis (EPO) and EPO receptor production, then promote the maturation of Hb-filled red blood cells [13]. In addition, it can improve the utilization of iron by reducing hepcidin and increasing iron transport to the bone marrow to improve anemia[14].
Six agents of HIF-PHIs have been reported, including Roxadustat, Daprodustat, Vadadustat, Molidustat, Enarodustat, and Desidustat. Some have been approved for treating CKD-related anemia in China, the EU, United Kindom, and Japan[15, 16]. A meta-analysis of randomized controlled trials including 6518 patients showed that Roxadustat could effectively remedy anemia in DD-CKD patients compared with ESAs, reduce cardiac failure and increase the risk of hypotension, vomiting, and arteriovenous fistula thrombosis[17]. Another meta-analysis of 7 trials including 7,933 patients, indicated that Daprodustat might have a better impact on dialysis-dependent (DD) patients in optimizing iron metabolism despite being non-inferior in improving anemia in both DD and nondialysis-dependent (NDD) patients[18]. Numerous studies have shown the efficacy of HIF-PHI in improving anemia. Still, security concerns were not the focus, and each agent of HIF-PHIs behaves slightly differently. There is a lack of direct comparison between them, which restricts the clinical application of these agents. 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.