维达列汀治疗透析患者贫血的安全性和疗效。
Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.
机构信息
From the Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin (K.-U.E.); the Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis (R.A.); Gonzalez M.D. and Aswad M.D. Health Care Services, Miami (A. Aswad); Clinical Research Consultants, Kansas City, MO (A. Awad); U.S. Renal Care, Plano (G.A.B.), Baylor University Medical Center, Baylor Heart and Vascular Hospital, Baylor Heart and Vascular Institute, Dallas (P.A.M.), Renal Associates, Division of Nephrology, University of Texas Health Science Center at San Antonio, San Antonio (P.P.), and the Section of Nephrology, Baylor College of Medicine, Houston (W.C.W.) - all in Texas; Praxis Medical Research, and the Department of Medicine, Division of General Practice, Faculdade de Medicina do ABC, São Paulo (M.R.B.); Akebia Therapeutics, Cambridge (Y.M.K.F., Z.K., B.J.M., W.L., D.L.V.), and the Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston (M.J.S.) - both in Massachusetts; the Division of Nephrology, Department of Medicine, Hofstra Northwell School of Medicine, Great Neck (S.F.), and the Division of Nephrology, New York Presbyterian, Queens (B.S.) - both in New York; Nephrology Associates, Augusta (H.H.), and Emory University School of Medicine, Atlanta (J.T.) - both in Georgia; the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.J.); the Department of Medicine, Vanderbilt University Medical Center, Nashville (M.J.K.); the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore (K.M.); Stanford University School of Medicine, Palo Alto, CA (E.F.L., G.M.C.); the Department of Medicine, Memorial University, St. John's, NL, Canada (P.S.P.); Statistics Collaborative, Washington, DC (K.A.W., J.W.); and the Department of Kidney Transplantation-Dialysis Department, Barlicki Memorial Teaching Hospital No. 1, Medical University of Lodz, Lodz, Poland (R.Z.).
出版信息
N Engl J Med. 2021 Apr 29;384(17):1601-1612. doi: 10.1056/NEJMoa2025956.
BACKGROUND
Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production.
METHODS
We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter).
RESULTS
A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively.
CONCLUSIONS
Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNOVATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).
背景
vadadustat 是一种口服低氧诱导因子脯氨酰羟化酶抑制剂，属于一类能刺激内源性促红细胞生成素产生的化合物。
方法
我们进行了两项随机、开放标签、非劣效性 3 期试验，以评估 vadadustat 与 darbepoetin alfa 在伴有贫血和新发或已确诊透析依赖型慢性肾脏病（DD-CKD）的患者中的安全性和疗效。主要安全性终点为首次发生主要不良心血管事件（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终点），在两项试验中汇总评估（非劣效性边界为 1.25）。主要次要安全性终点为 MACE 加上心力衰竭或血栓栓塞事件住院的首次发生。主要和关键次要疗效终点分别为每个试验中从基线到第 24 周到 36 周以及从基线到第 40 周到 52 周时血红蛋白的平均变化，分别为（非劣效性边界为 -0.75 g/dL）。
结果
共有 3923 例患者以 1:1 的比例随机分配接受 vadadustat 或 darbepoetin alfa 治疗：369 例患者在新发 DD-CKD 试验中，3554 例患者在已确诊 DD-CKD 试验中。在汇总分析中，vadadustat 组有 355 例（18.2%）患者发生首次 MACE，darbepoetin alfa 组有 377 例（19.3%）患者发生首次 MACE（风险比，0.96；95%置信区间[CI]，0.83 至 1.11）。在第 24 周到 36 周时，两组间血红蛋白浓度的平均差异为 -0.31 g/dL（95%CI，-0.53 至 -0.10），在第 40 周到 52 周时为 -0.07 g/dL（95%CI，-0.34 至 0.19）。在新发 DD-CKD 试验中，vadadustat 组分别为 -0.17 g/dL（95%CI，-0.23 至 -0.10）和 -0.18 g/dL（95%CI，-0.25 至 -0.12），在已确诊 DD-CKD 试验中分别为 -0.17 g/dL（95%CI，-0.23 至 -0.10）和 -0.18 g/dL（95%CI，-0.25 至 -0.12）。vadadustat 组严重不良事件的发生率在新发 DD-CKD 试验中为 49.7%，在已确诊 DD-CKD 试验中为 55.0%，darbepoetin alfa 组的发生率分别为 56.5%和 58.3%。
结论
在接受透析的贫血和 CKD 患者中，vadadustat 与 darbepoetin alfa 相比在心血管安全性和血红蛋白浓度的纠正及维持方面不劣效。（由 Akebia Therapeutics 和 Otsuka Pharmaceutical 资助；INNOVATE 临床试验.gov 编号，NCT02865850 和 NCT02892149。）
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