{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T16:10:19Z","timestamp":1784736619713,"version":"3.55.0"},"reference-count":38,"publisher":"American Medical Association (AMA)","issue":"15","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2025,10,21]]},"abstract":"Importance<\/jats:title>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.<\/jats:p><\/jats:sec>Objective<\/jats:title>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.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>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.<\/jats:p><\/jats:sec>Interventions<\/jats:title>Participants were randomized to receive everolimus and low-dose tacrolimus (n\u2009=\u2009107) or standard-dose tacrolimus and mycophenolate mofetil (n\u2009=\u2009104) for 30 months.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>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.<\/jats:p><\/jats:sec>Results<\/jats:title>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, \u22120.32; 95% CI, \u22120.90 to 0.20; P<\/jats:italic>\u2009=\u2009.16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, \u22120.40; 95% CI, \u22121.81 to 0.93), meeting the success criterion for safety (noninferiority margin &amp;lt;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<\/jats:sup>; 95% CI, 1.09-19.91 mL\/min\/1.73 m2<\/jats:sup>) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>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.<\/jats:p><\/jats:sec>Trial Registration<\/jats:title>ClinicalTrials.gov Identifier: NCT03386539<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jama.2025.14338","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T15:00:35Z","timestamp":1758121235000},"page":"1339","source":"Crossref","is-referenced-by-count":3,"title":["Everolimus and Low-Dose Tacrolimus After Heart Transplant in Children"],"prefix":"10.1001","volume":"334","author":[{"given":"Christopher S.","family":"Almond","sequence":"first","affiliation":[{"name":"Department of Pediatrics (Cardiology), Stanford University School of Medicine, Palo Alto, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin P.","family":"Daly","sequence":"additional","affiliation":[{"name":"Department of 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