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

Abstract

Importance: 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.

Objective: 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.

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

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. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.

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. 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).

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. 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.

Trial registration: ClinicalTrials.gov Identifier: NCT03386539.

Figure 1.. Participant Flow in the TEAMMATE Trial

Figure 2.. Primary Outcomes of the TEAMMATE Trial

ACR indicates acute cellular rejection; AMR, antibody-mediated rejection; CAV, cardiac allograft vasculopathy; CKD, chronic kidney disease; CMV, cytomegalovirus; MATE, major adverse transplant event; and PTLD, posttransplant lymphoproliferative disorder. A, The primary efficacy outcome was the MATE-3 score, the cumulative burden of 3 MATEs (ACR, CAV, and CKD) at 30 months. Time-related changes in the mean MATE-3 score through 30 months are shown. The mean 30-month MATE-3 scores for the everolimus and mycophenolate groups were not significantly different (everolimus, 0.9 [SD, 2.2]; mycophenolate, 1.3 [SD, 2.5]; mean difference, −0.32; 95% CI, −0.90 to 0.20; P = .16). The mean subscores shown above the graph combine to form the total MATE-3 score at the 30 months. B, The primary safety outcome was the MATE-6 score, the cumulative burden of 6 MATEs (MATE-3 events plus AMR, infection, and PTLD) at 30 months. Time-related changes in the mean MATE-6 score through 30 months are shown. The mean 30-month MATE-6 score was no higher in the everolimus group than in the mycophenolate group (everolimus, 2.0 [SD, 4.6]; mycophenolate, 2.4 [SD, 5.2]; mean difference, −0.40; 95% CI, −1.81 to 0.93; noninferiority margin, <3), meeting the success criterion for safety. The mean subscores shown above the graph combine to form the total MATE-6 score at 30 months. C, The cumulative burden of 3 MATEs (ACR, CAV, and CKD) plus CMV infection was a post hoc outcome. Time-related changes in the mean MATE-3 + CMV score through 30 months are shown. At 30 months, the mean score for the everolimus group was lower than for the mycophenolate group (mean difference, −0.45; 95% CI, −1.07 to −0.01; P = .03). The mean subscores shown above the graph combine to form the total MATE-3 + CMV score at 30 months.

Figure 3.. Exploratory End Points

eGFR indicates estimated glomerular filtration rate. A, The box-and-whisker plot shows mean eGFR values by treatment group. Center lines in the boxes indicate medians; box tops and bottoms, IQRs. Whiskers extend to the most extreme data points on either side of the boxes within 1.5 times the IQRs. Outliers are shown as dots outside the whiskers. Mean eGFR values are indicated by dots inside the boxes, connected by lines to demonstrate how the treatment group means change over time. The 95% CI for the mean difference did not include zero at 3, 6, 12, and 18 months after randomization, when the everolimus group means were higher than the mycophenolate group means. Values above 260 mL/min/1.73 m² are not shown. B, Baseline-adjusted eGFR from piecewise linear-fit model. The slopes for eGFR from 0 months to 6 months differ by treatment group (2.78 [SE, 0.47] for everolimus and 1.39 [SE, 0.48] for mycophenolate; slope difference, 1.39; 95% CI, 0.10-2.70). The slopes for eGFR from 6 months to 30 months do not differ by treatment group (−0.38 [SE, 0.12] for everolimus and −0.21 [SE, 0.12] for mycophenolate; slope difference, −0.17; 95% CI, −0.50 to 0.16). C, Cumulative incidence of cytomegalovirus infection through 33 months by treatment group. D, Proportion of participants who developed anti-HLA antibodies by treatment group. Risk difference at 0 months, −5.0% (95% CI, −14.7% to 4.7%); at 6 months, −12.7% (95% CI, −22.0% to −3.3%); at 18 months, −7.9% (95% CI, −18.2% to 2.4%); and at 30 months, −13.1% (95% CI, −25.4% to −0.8%).