Everolimus and Low-Dose Tacrolimus After Heart Transplant in Children: A Randomized Clinical Trial.

Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant.

由于引入依维莫司后新发感染导致的死亡率数据较高，依维莫司的使用因此存在争议。

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.

目前尚不清楚在移植后6个月开始使用依维莫司对于儿童是否安全有效，这是一个中位移植物存活时间仅限于15年的群体，且缺乏随机临床试验。

Background

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.

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。

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.

设计、设置和参与者：一项多中心、随机、开放标签的临床试验，招募了211名在2018年2月至2020年8月期间，于美国25个地点接受儿童心脏移植后6个月仍然存活的患者。

The last date of follow-up was April 17, 2023.

最后的随访日期是2023年4月17日。

Methods

Participants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.

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吗替麦考酚酯(n = 104)治疗，为期30个月。

main_outcomes_and_measures

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.

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复合序数终点，包括急性细胞性排斥反应、CAV和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.

主要安全性终点是MATE-6评分，包括MATE-3评分、抗体介导的排斥反应、感染和移植后淋巴增殖性疾病。

Results

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.

在随机分配的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个月内接受过排斥反应治疗。

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).

在30个月时，两治疗组的平均MATE-3评分没有差异（平均差异，-0.32；95%置信区间，-0.90至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).

在依维莫司组与吗替麦考酚酯组之间，平均MATE-6评分没有更高（基线调整后的平均差异，-0.40；95%置信区间，-1.81至0.93），满足了安全性的成功标准（非劣效性边界<3）。

There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE.

在移植物存活率、MATE自由生存期或任何个别MATE的无病生存期方面没有差异。

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 incidenceof CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).

在12个月时，依维莫司与估算肾小球滤过率的更大改善（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）和较低的CMV感染发生率（风险比，0.50；95%置信区间，0.26-0.93）相关。

conclusions_and_relevance

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.

在6个月存活的儿科心脏移植患者中，依维莫司和低剂量他克莫司与他克莫司和吗替麦考酚酯在预防30个月时的细胞排斥反应、冠状动脉血管病变（CAV）和慢性肾脏病（CKD）的复合终点方面没有差异。

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.

然而，基于6个月MATEs总负担，依维莫司和低剂量他克莫司似乎安全，并可能与改善的肾功能和较少的CMV感染相关。

trial_registration

ClinicalTrials.gov Identifier: NCT03386539.

临床试验注册号：NCT03386539。