<p>Anticoagulation in children is problematic for multiple reasons. Currently used anticoagulants have significant disadvantages and may negatively affect quality of life (QOL). This manuscript describes the design, rationale, and methods of a prospective, randomized, open label phase II multi-national clinical trial of a direct oral anticoagulant (DOAC), apixaban, in children and infants with congenital and acquired heart disease. This trial is designed to gather preliminary safety and pharmacokinetics (PK) data, as well as generate data on QOL of individuals taking apixaban compared to the standard of care (SOC) anticoagulants vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). A key issue this trial seeks to address is the practice of using therapeutics tested in adult trials in the pediatric population without robust pediatric safety or efficacy data. Pediatric heart diseases are not common, and specific diagnoses often meet the criteria of a rare disease; thus, statistical efficacy may be difficult to achieve. This trial will provide valuable PK and safety data intended to inform clinical practice for anticoagulation in pediatric heart diseases, a setting in which a fully powered phase III clinical trial is not feasible. A second consideration this trial addresses is that metrics besides efficacy, such as QOL, have not been traditionally used as endpoints in regulated anticoagulation studies yet may add substantial weight to the clinical decision for use of a DOAC in place of VKA or LMWH. This study examines QOL related to both heart disease and anticoagulation among children randomized to either SOC or apixaban. There are considerable strengths and benefits to conducting a clinical trial in pediatric rare disease populations via an industry-academic collaboration. The SAXOPHONE study represents a collaboration between Bristol-Myers Squibb (BMS)/Pfizer Alliance, and the National Heart, Lung, and Blood Institute's (NHLBI) Pediatric Heart Network (PHN) and may be an attractive model for future pediatric drug trials.</p>

<p><strong>BACKGROUND: </strong>The Pediatric Heart Network designed a career development award to train the next generation of clinician scientists in paediatric-cardiology-related research, a historically underfunded area. We sought to identify the strengths/weaknesses of the programme and describe the scholars' academic achievements and the network's return on investment.</p>

<p><strong>METHODS: </strong>Survey questions designed to evaluate the programme were sent to applicants - 13 funded and 19 unfunded applicants - and 20 mentors and/or principal investigators. Response distributions were calculated. χ2 tests of association assessed differences in ratings of the application/selection processes among funded scholars, unfunded applicants, and mentors/principal investigators. Scholars reported post-funding academic achievements.</p>

<p><strong>RESULTS: </strong>Survey response rates were 88% for applicants and 100% for mentor/principal investigators. Clarity and fairness of the review were rated as "clear/fair" or "very clear/very fair" by 98% of respondents, but the responses varied among funded scholars, unfunded applicants, and mentors/principal investigators (clarity χ2=10.85, p=0.03; fairness χ2=16.97, p=0.002). Nearly half of the unfunded applicants rated feedback as "not useful" (47%). "Expanding their collaborative network" and "increasing publication potential" were the highest-rated benefits for scholars. Mentors/principal investigators found the programme "very" valuable for the scholars (100%) and the network (75%). The 13 scholars were first/senior authors for 97 abstracts and 109 manuscripts, served on 22 Pediatric Heart Network committees, and were awarded $9,673,660 in subsequent extramural funding for a return of ~$10 for every scholar dollar spent.</p>

<p><strong>CONCLUSIONS: </strong>Overall, patient satisfaction with the Scholar Award was high and scholars met many academic markers of success. Despite this, programme challenges were identified and improvement strategies were developed.</p>

<p><strong>BACKGROUND: </strong>Significant disparities exist between patients of different races and with different family incomes; less is understood regarding community-level factors on outcomes.</p>

<p><strong>METHODS: </strong>In this study, we used linked data from the Pediatric Health Information System database and the US Census Bureau to examine associations between median annual household income by zip code and mortality, length of stay, inpatient standardized costs, and costs per day, over and above the effects of race and payer, first for children undergoing cardiac surgery (2005-2015) and then for all pediatric discharges (2012-2015). Median community-level income was examined as continuous and categorical (by quartile) predictors. Hierarchical logistic and censored linear regression models were constructed. To these models, patient and surgical characteristics, year, race, payer, state, urban or rural designation, and center fixed effects were added.</p>

<p><strong>RESULTS: </strong>We identified 101 013 cardiac surgical (and 857 833 total) hospitalizations from 46 institutions. Children from the lowest-income neighborhoods who were undergoing cardiac surgery had 1.18 times the odds of mortality (95% confidence interval [CI]: 1.03 to 1.35), 7% longer lengths of stay (CI: 1% to 14%), and 7% higher standardized costs (CI: 1% to 14%) than children from the highest-income neighborhoods. Results for all children were similar, both with and without any major chronic conditions. The effects of neighborhood were only partially explained by differences in race, payer, or the centers at which patients received care. There were no differences in costs per day.</p>

<p><strong>CONCLUSIONS: </strong>Children from lower-income neighborhoods are at increased risk of mortality and use more resource intensive care than children from higher-income communities, even after accounting for disparities between races, payers, and centers.</p>