美国布列根和妇女医院Ajay K. Singh团队研究了达普司他治疗透析患者贫血的疗效。该研究于2021年11月5日发表在《新英格兰医学杂志》上。

在慢性肾病（CKD）患者中，使用重组人红细胞生成素及其衍生物治疗贫血可能增加中风、心肌梗死和其他不良事件的风险。一些试验表明，缺氧诱导因子（HIF）脯氨酰羟化酶抑制剂（PHIs）在提高血红蛋白水平方面与红细胞生成刺激剂（ESA）一样有效。

在这项随机、开放标签的临床3期试验中，研究组招募正在接受透析且血红蛋白水平为8.0至11.5 g/dL的CKD患者，接受口服HIF-PHI（达普司他片）或注射ESA（若正在接受血液透析，则服用阿法依泊汀；若正在接受腹膜透析，则服用阿法达贝泊）。两个主要结局为从基线检查到第28-52周血红蛋白水平的平均变化（非劣效性边缘为−0.75 g/dL）和首次发生重大心血管不良事件（全因死亡、非致命性心肌梗死或非致命性中风的综合），非劣效性范围为1.25。

共有2964名患者接受了随机分组。平均基线血红蛋白水平为10.4 g/dL。达普司他组从基线检查到第28-52周的血红蛋白水平的平均变化为0.28 g/dL，ESA组为0.10 g/dL，相差0.18 g/dL，符合预先规定的非劣效性范围。在2.5年的中位随访期间，达普司他组1487名患者中有374名（25.2%）发生重大心血管不良事件，ESA组1477名患者中有394名（26.7%），风险比为0.93，这也符合达普司他预先规定的非劣效性范围。两组中发生其他不良事件的患者比例相似。

研究结果表明，在接受透析的CKD患者中，达普司他在血红蛋白水平相对于基线水平的变化和心血管结局方面并不比ESA差。

附：英文原文

Title: Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis | NEJM

Author: Ajay K. Singh, M.B., B.S., M.B.A.,, Kevin Carroll, Ph.D.,, Vlado Perkovic, M.B., B.S.,, Scott Solomon, M.D.,, Vivekanand Jha, M.D.,, Kirsten L. Johansen, M.D.,, Renato D. Lopes, M.D., Ph.D.,, Iain C. Macdougall, M.D.,, Gregorio T. Obrador, M.D.,, Sushrut S. Waikar, M.D.,, Christoph Wanner, M.D.,, David C. Wheeler, M.B., Ch.B., M.D.,, Andrzej Wicek, M.D., Ph.D.,, Allison Blackorby, M.Sc.,, Borut Cizman, M.D.,, Alexander R. Cobitz, M.D., Ph.D.,, Rich Davies, M.Sc.,, Jo Dole, Ph.D.,, Lata Kler, Ph.D.,, Amy M. Meadowcroft, Pharm.D.,, Xinyi Zhu, M.Sc.,, and John J.V. McMurray, M.D.

Issue&Volume: 2021-11-05

Abstract:

Background

Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are as effective as erythropoiesis-stimulating agents (ESAs) in increasing hemoglobin levels.

Methods

In this randomized, open-label, phase 3 trial, we assigned patients with CKD who were undergoing dialysis and who had a hemoglobin level of 8.0 to 11.5 g per deciliter to receive an oral HIF-PHI (daprodustat) or an injectable ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The two primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, 0.75 g per deciliter) and the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25.

Results

A total of 2964 patients underwent randomization. The mean (±SD) baseline hemoglobin level was 10.4±1.0 g per deciliter overall. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per deciliter in the daprodustat group and 0.10±0.02 g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of 0.75 g per deciliter. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups.

Conclusions

Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes.

DOI: 10.1056/NEJMoa2113379

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2113379