Lipsitz, Stuart R.

ImportanceStudies 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.ObjectiveTo 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 ParticipantsMulticenter, 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.InterventionsParticipants 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 MeasuresThe 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.ResultsAmong 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 RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT03386539

Background: End-of-life (EOL) care intensity is known to vary by secular and geographic patterns. US physicians receive less aggressive EOL care than the general population, presumably the result of preferences shaped by work-place experience with EOL care. Objective: We investigated occupation as a source of variation in EOL care intensity. Methods: Across 4 states, we identified 660 599, nonhealth maintenance organization Medicare beneficiaries aged ≥66 years who died between 2004 and 2011. Linking death certificates, we identified beneficiaries with prespecified occupations: nurses, farmers, clergy, mortuary workers, homemakers, first-responders, veterinary workers, teachers, accountants, and the general population. End-of-life care intensity over the last 6 months of life was assessed using 5 validated measures: (1) Medicare expenditures, rates of (2) hospice, (3) surgery, (4) intensive care, and (5) in-hospital death. Results: Occupation was a source of large variation in EOL care intensity across all measures, before and after adjustment for sex, education, age-adjusted Charlson Comorbidity Index, race/ethnicity, and hospital referral region. For example, absolute and relative adjusted differences in expenditures were US$9991 and 42% of population mean expenditure ( P < .001 for both). Compared to the general population on the 5 EOL care intensity measures, teachers (5 of 5), homemakers (4 of 5), farmers (4 of 5), and clergy (3 of 5) demonstrated significantly less aggressive care. Mortuary workers had lower EOL care intensity (4 of 5) but small numbers limited statistical significance. Conclusion: Occupations with likely exposure to child development, death/bereavement, and naturalistic influences demonstrated lower EOL care intensity. These findings may inform patients and clinicians navigating choices around individual EOL care preferences.

SummaryClinical trials often include binary end points. In some cases, no successes are observed and the usual large sample estimates of relative risk are undefined. The paper proposes an estimator for relative risk based on the median unbiased estimator. The relative risk estimator proposed is well defined and performs satisfactorily for a wide range of data configurations. To facilitate the use of the estimator, a deterministic bootstrap confidence interval is also proposed, and an SAS macro is available to perform the necessary calculations. An on-going randomized clinical trial motivated the development of the estimator and is used to illustrate the approach.