Minutolo Roberto, Liberti Maria Elena, Simeon Vittorio, Sasso Ferdinando C, Borrelli Silvio, De Nicola Luca, Garofalo Carlo
Nephrology Unit, University of Campania "Luigi Vanvitelli", Naples, Italy.
Medical Statistic Unit, University of Campania "Luigi Vanvitelli", Naples, Italy.
Clin Kidney J. 2023 Jun 22;17(1):sfad143. doi: 10.1093/ckj/sfad143. eCollection 2024 Jan.
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new therapeutic agents for anaemia in chronic kidney disease (CKD). We evaluated by meta-analysis and meta-regression the efficacy and safety of HIF-PHIs in patients with CKD-related anaemia.
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), arterovenous fistula (AVF) thrombosis and death.
We included 26 RCTs with 24 387 patients. Random effect meta-analysis of the 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 to 0.17). Meta-regression analysis showed a significantly higher haemoglobin change for HIF-PHIs in younger patients and versus short-acting ESA (0.21 g/dL, 95% CI 0.12 to 0.29 versus -0.01, 95% CI -0.09 to 0.07 in studies using long-acting ESA, < .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, = .020). Rate ratio of cancer (0.93, 95% CI 0.76 to 1.13), MACE (1.00, 95% CI 0.94 to 1.07), MACE+ (1.01, 95% CI 0.95 to 1.06), thrombotic events (1.08, 95% CI 0.84 to 1.38), AVF thrombosis (1.02, 95% CI 0.93 to 1.13) and death (1.02, 95% CI 0.95 to 1.13) did not differ between HIF-PHIs and ESAs.
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.
缺氧诱导因子脯氨酰羟化酶抑制剂（HIF-PHIs）是治疗慢性肾脏病（CKD）贫血的新型治疗药物。我们通过荟萃分析和荟萃回归评估了HIF-PHIs治疗CKD相关性贫血患者的疗效和安全性。
我们选择了在透析和非透析患者中比较HIF-PHIs与促红细胞生成剂（ESAs）的3期随机临床试验（RCTs）。疗效指标包括血红蛋白、铁参数（铁调素、血清铁、总铁结合力、转铁蛋白饱和度、铁蛋白）和静脉铁剂剂量相对于基线的变化；作为安全性指标，我们考虑癌症、判定的主要不良心血管事件（MACE）、MACE+（MACE加因心力衰竭或不稳定型心绞痛或血栓栓塞事件住院）、血栓形成事件（深静脉血栓形成、肺栓塞）、动静脉内瘘（AVF）血栓形成和死亡。
我们纳入了26项RCTs，共24387例患者。对HIF-PHIs与ESAs之间未标准化均值差的随机效应荟萃分析显示，血红蛋白水平相对于基线有显著变化，为0.10g/dL（95%CI 0.02至0.17）。荟萃回归分析显示，在年轻患者中以及与短效ESA相比，HIF-PHIs引起的血红蛋白变化显著更高（0.21g/dL，95%CI 0.12至0.29，而在使用长效ESA的研究中为-0.01，95%CI -0.09至0.07，P<0.001）。未发现HIF-PHIs类型对异质性有显著影响。与ESAs相比，HIF-PHIs可使铁调素和铁蛋白显著下降，血清铁和总铁结合力显著升高，而转铁蛋白饱和度未改变；HIF-PHI治疗时静脉铁剂剂量更低（-3.1mg/周，95%CI -5.6至-0.6，P=0.020）。HIF-PHIs与ESAs在癌症（0.93，95%CI 0.76至1.13）、MACE（1.00，95%CI 0.94至1.0；MACE+（1.01，95%CI）、血栓形成事件（1.08，95%CI 0.84至1.38）、AVF血栓形成（1.02，95%CI 0.93至1.13）和死亡（1.02，95%CI 0.95至1.13）的发生率比值方面无差异。
与ESA治疗相比，所选用于比较的剂量的HIF-PHIs在纠正贫血方面有效，对铁代谢有显著影响，且不同药物之间无明显差异。使用HIF-PHIs未出现安全性信号。
