Winkelmayer Wolfgang C, Arnold Susan, Burke Steven K, Chertow Glenn M, Eckardt Kai-Uwe, Jardine Alan G, Lewis Eldrin F, Luo Wenli, Matsushita Kunihiro, McCullough Peter A, Minga Todd, Parfrey Patrick S
Section of Nephrology, Baylor College of Medicine, Houston, TX.
Excellentis Clinical Trial Consultants, South Africa.
Kidney Med. 2023 May 12;5(7):100666. doi: 10.1016/j.xkme.2023.100666. eCollection 2023 Jul.
RATIONALE & OBJECTIVE: Prespecified analyses of the PROTECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PROTECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents.
Phase 3, global, open-label, randomized, active-controlled clinical trial.
Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD.
Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa.
The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis).
In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of ≤10 mL/min/1.73 m in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of ≤10 mL/min/1.73 m and who may not have had access to dialysis.
Different regional treatment patterns of patients with NDD-CKD.
The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths.
预先设定的对PROTECT试验的分析比较了口服低氧诱导因子脯氨酰羟化酶抑制剂vadadustat与阿法依泊汀在非透析依赖型慢性肾脏病（NDD-CKD）患者中的安全性，结果发现美国患者的主要不良心血管事件（MACE；任何原因导致的死亡或非致命性心肌梗死或中风）无差异，而在美国以外接受vadadustat治疗的患者中风险更高。我们调查了在纳入1751例既往未接受促红细胞生成素刺激剂治疗的患者的PROTECT试验中MACE的地区差异。
3期、全球、开放标签、随机、活性对照临床试验。
未接受促红细胞生成素刺激剂治疗的贫血和NDD-CKD患者。
符合条件的患者按1:1随机分组，接受vadadustat或阿法依泊汀。
主要安全终点是首次发生MACE的时间。次要安全终点包括首次发生扩展MACE（MACE加因心力衰竭或血栓栓塞事件住院，不包括血管通路血栓形成）的时间。
在非美国/非欧洲地区，vadadustat组基线估计肾小球滤过率（eGFR）水平≤10 mL/min/1.73 m²的患者比例[96例（34.7%）]高于阿法依泊汀组[66例（24.0%）]。在该地区，vadadustat组报告的MACE事件比阿法依泊汀组多21例[78例（n = 276）对57例（n = 275）]，包括多13例非心血管死亡，主要死于肾衰竭。非心血管死亡集中在巴西和南非，这两个国家纳入的eGFR≤10 mL/min/1.73 m²的患者比例较高，且可能无法进行透析。
NDD-CKD患者的地区治疗模式不同。
非美国/非欧洲vadadustat组较高的MACE发生率可能部分归因于在透析服务不均衡的国家中基线eGFR水平的不平衡，导致许多与肾脏相关的死亡。
