Almond Christopher S, Daly Kevin P, Albers Erin L, Alejos Juan C, Ameduri Rebecca, Auerbach Scott R, Barkoff Lynsey, Barnes Aliessa P, Bock Matthew J, Butto Arene, Carlo Waldemar F, Castleberry Chesney D, Chrisant Maryanne R, Deshpande Shriprasad R, Dreyer William J, Everitt Melanie D, Feingold Brian, Gonzales Selena, Hollander Seth A, Kindel Steven J, Klein Gloria L, Lal Ashwin K, Lamour Jacqueline M, Lee Joanne, Lu Minmin, Lytrivi Irene D, Miyamoto Shelley D, Pahl Elfriede, Peng David M, Ryan Thomas D, Singh Tajinder P, Su Jennifer A, Sutcliffe David L, Ybarra A Marian, Zangwill Steven, Rossano Joseph W, Sleeper Lynn A
Department of Pediatrics (Cardiology), Stanford University School of Medicine, Palo Alto, California.
Department of Cardiology, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
JAMA. 2025 Oct 21;334(15):1339-1348. doi: 10.1001/jama.2025.14338.
Studies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.
To evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant.
DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023.
Participants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.
The primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.
Among 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, -0.32; 95% CI, -0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, -0.40; 95% CI, -1.81 to 0.93), meeting the success criterion for safety (noninferiority margin <3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).
Among 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection.
ClinicalTrials.gov Identifier: NCT03386539.
研究表明，依维莫司可能会降低心脏移植后排异反应、心脏移植血管病变（CAV）、慢性肾脏病（CKD）和巨细胞病毒（CMV）感染的风险。由于有数据显示移植后从头开始使用依维莫司会导致更高的感染死亡风险，因此依维莫司的使用存在争议。对于儿童患者，在移植后6个月开始使用依维莫司是否安全有效尚不清楚，该人群的移植心脏中位生存期仅为15年，且缺乏随机临床试验。
评估依维莫司联合低剂量他克莫司预防儿童心脏移植后主要不良移植事件（MATEs）的安全性和有效性。
设计、地点和参与者：多中心、随机、开放标签的临床试验，纳入了2018年2月至2020年8月在美国25个地点接受小儿心脏移植且术后6个月仍存活的211名患者。最后一次随访日期为2023年4月17日。
参与者被随机分配接受依维莫司和低剂量他克莫司（n = 107）或标准剂量他克莫司和霉酚酸酯（n = 104），疗程为30个月。
主要疗效终点是30个月时的MATE-3评分，这是一个经过验证的综合有序终点，包括急性细胞排斥反应、CAV和CKD。主要安全终点是MATE-6评分，包括MATE-3评分加上抗体介导的排斥反应、感染和移植后淋巴细胞增生性疾病。
在随机分组的211名儿童中，平均年龄为8.2（标准差，6.3）岁，97名（46%）因先天性心脏病接受移植，49名（23%）在6个月前接受过排斥反应治疗。在30个月时，两个治疗组的平均MATE-3评分无差异（平均差异，-0.32；95%置信区间，-0.90至0.20；P = 0.16）。依维莫司组的平均MATE-6评分不高于霉酚酸酯组（基线调整后的平均差异，-0.40；95%置信区间，-1.81至0.93），达到了安全性成功标准（非劣效界值<3）。在移植心脏存活率、无MATE生存期或无任何个体MATE方面无差异。依维莫司与12个月时估计肾小球滤过率的更大改善相关（平均差异，10.5 mL/min/1.73 m²；95%置信区间，1.09 - 19.91 mL/min/1.73 m²），且CMV感染发生率较低（风险比，0.50；95%置信区间，0.26 - 0.93）。
在小儿心脏移植术后6个月的幸存者中，依维莫司和低剂量他克莫司在预防30个月时的细胞排斥反应、CAV和CKD综合情况方面与他克莫司和霉酚酸酯无差异。然而，基于6种MATEs的总体负担，依维莫司和低剂量他克莫司似乎是安全的，并且可能与肾功能改善和CMV感染减少有关。
ClinicalTrials.gov标识符：NCT03386539。
