Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD
Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD
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DOI：
10.1056/nejmoa2035938
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发表时间：
2021-04-29
影响因子：
158.5
通讯作者：
Eckardt, Kai-Uwe
中科院分区：
文献类型：
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作者：
Chertow, Glenn M.;Pergola, Pablo E.;Eckardt, Kai-Uwe
Vadadustat是一种口服缺氧诱导因子（HIF）脯氨酰羟化酶抑制剂，一类稳定HIF并刺激促红细胞生成素和红细胞生成的药物。方法在两项3期随机、开放标签、主动对照、非劣效性试验中，我们比较了vadadustat和促红细胞生成剂（ESA） darbepoetin在非透析依赖性慢性肾脏疾病（NDD-CKD）患者（以前未接受过ESA治疗且血红蛋白浓度低于10 g /分升）和ESA治疗的NDD-CKD患者（血红蛋白浓度为8 - 11 g /分升（在美国）或9 - 12 g /分升（在其他国家））中的应用。在事件发生时间分析中评估的主要安全性终点是两项试验中首次发生的主要心血管不良事件（MACE，任何原因导致的死亡、非致死性心肌梗死或非致死性卒中的复合死亡）。次要安全终点包括扩大的MACE （MACE加上心力衰竭或血栓栓塞事件的住院治疗）。每项试验的主要和关键的次要疗效终点是在两个评估期间（第24周到36周和第40周到52周）血红蛋白浓度相对基线的平均变化。结果在两项试验中，共有1751例未经esa治疗的NDD-CKD患者和1725例接受esa治疗的NDD-CKD患者进行了随机分组。在合并分析中，有1739例患者接受了vadadustat， 1732例患者接受了darbepoetin， MACE的风险比为1.17(95%可信区间[CI]， 1.01 ~ 1.36)，未达到预先设定的1.25的非劣效性裕度。第24至36周，未接受esa治疗的患者血红蛋白浓度变化的组间平均差异为0.05 g /分升（95% CI, -0.04至0.15），接受esa治疗的患者血红蛋白浓度变化的组间平均差异为-0.01 g /分升（95% CI, -0.09至0.07），符合预先设定的-0.75 g /分升的非劣效性界限。结论Vadadustat与darbepoetin相比，符合NDD-CKD患者血液疗效的非劣效性标准，但不符合心血管安全性的非劣效性标准。（由Akebia Therapeutics和Otsuka Pharmaceutical资助；PRO2TECT ClinicalTrials.gov编号：NCT02648347和NCT02680574。）两项随机、3期、开放标签的非效性试验比较了Vadadustat与达贝泊汀在非透析依赖性慢性肾病患者中的疗效。Vadadustat与darbepoetin相比，在血液学疗效方面符合预定的非劣效性标准，但在心血管安全性方面不符合。
Background Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production.Methods In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52.Results A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter.Conclusions Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.)Vadadustat in Non-Dialysis-Dependent CKD Two randomized, phase 3, open-label noninferiority trials compared vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease. Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not for cardiovascular safety.