Systematic review on the design and methodology of the pediatric direct oral anticoagulant clinical trials for thrombosis prevention: communication from the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis.

BACKGROUND

Prevention of thromboembolism (TE) remains a priority in children with a high thrombotic risk. While recent trials using direct oral anticoagulants (DOACs) for TE prevention have been completed, these trials had significant limitations.

OBJECTIVES

This study reviewed the methodology of pediatric DOAC trials for TE prevention to identify design and execution challenges and opportunities for improvement.

METHODS

We performed a systematic review of MEDLINE, EMBASE, the Cochrane Library, and clinicaltrials.gov, from January 2002 to April 2025, to identify pediatric trials evaluating DOACs for TE prevention. We compared registered information in clinicaltrials.gov, trial design manuscripts, and final result manuscripts of pivotal TE prevention DOAC trials to highlight changes in methods, study duration, and outcomes.

RESULTS

Eight publications from 4 trials (1 design and 1 final manuscript each) were included. Each trial targeted a pediatric subpopulation: 3 in cardiac disease and 1 in oncology. Together, 984 children enrolled in the 4 trials. All trials had some modification to methdology from original design, including changes in eligibility criteria, sample size, timing of end point ascertainment, outcomes, and analysis. All but 1 required a longer duration to complete than planned. Only 1 trial had definitive statistical power calculations.

CONCLUSION

The pediatric DOAC trials for TE prevention provide an opportunity to understand the unique successes and limitations in studying TE prevention in children. Given lack of power, inconsistent definitions, and limited follow-up duration, questions remain regarding safety, dose intensity, end points, and appropriate selection of high-risk populations. Future research should use innovative methods to overcome these limitations.