Systematic analysis of the design, methodology, and patient population characteristics of the pediatric direct oral anticoagulant trials of venous thromboembolism treatment

Background: The pediatric direct oral anticoagulation (DOAC) trials provide an opportunity to evaluate and characterize challenges in their design and execution to inform future antithrombotic trials. Objectives: To perform a systematic review of pediatric DOAC trials for the treatment of venous thromboembolism to critically appraise their methodology and understand the feasibility and challenges. Methods: We performed a systematic search of MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov (January 2002 to December 2022). Studies reporting the results of interventional trials of a DOAC for the treatment of acute venous thromboembolism in children and their respective design papers were included. Trial registration information was reviewed in ClinicalTrials.gov. Discrepancies in study design, targeted populations, sample size, and analyses between planned and actual trial conduct were examined qualitatively. Results: Five published studies and unpublished data for 2 additional trials were included. All trials had modifications to their design or methodology and discrepancies between the trial's registration and the final published study, suggesting feasibility challenges. Modifications to the eligibility criteria, changes in sample size, challenges with the recruitment of younger patients, and an enrolled population not matching the clinical target population were identified for all trials. Discrepancies in outcome reporting, particularly for secondary endpoints, were also common. Conclusion: DOAC trials experienced feasibility challenges that led to design or methodology modifications. Future pediatric antithrombotic trials will need to be adaptive in their design, prioritize enrollment of younger children and input from clinicians providing care to target populations, ensure that enrolled populations match the clinical population, and select clinically meaningful endpoints.