Anticoagulant prescribing trends, bleeding events, and reversal agent use in pediatric patients: A retrospective, real-world study

Abstract

This retrospective real-world study aimed to describe anticoagulant prescribing trends, particularly for factor Xa (FXa) inhibitors, bleeding events, and reversal agent use in pediatric patients to assess potential populations for clinical trials of the FXa inhibitor reversal agent andexanet alfa. Real-world health care data from the TriNetX Global Network and Optum's deidentified Clinformatics® Data Mart Database (CDM) were analyzed to identify patients aged <18 years old who were prescribed a direct oral FXa inhibitor, warfarin, or low-molecular-weight heparins from 2007 through 2024 (TriNetX, N = 59,780) or 2023 (CDM, N = 6470). The only anticoagulants prescribed to children were warfarin and/or low-molecular-weight heparins in 2007 and 2008 in TriNetX and from 2007 through 2010 in CDM. Prescriptions of the FXa inhibitor rivaroxaban increased from 0.4% (2009) to 18.0% (2023) in TriNetX and from 0.8% (2011) to 34.0% (2023) in CDM, with similar trends for apixaban. Relevant bleeding was reported in 9.4% of patients prescribed an FXa inhibitor in TriNetX; ≤ 0.1% of patients received andexanet alfa the day of a bleed. Among patients prescribed an FXa inhibitor, ≤ 0.1% in TriNetX and 0 in CDM received andexanet alfa the day of surgery. Direct oral FXa inhibitor use in children is growing, as is the potential for associated bleeds; however, reversal agent use is rare in this population. Given the possible unmet need and subsequent patient recruitment challenges, designing pediatric clinical trials of reversal agents requires innovative approaches.

Fig 1. Patient Cohort in TriNetX, comprising patients currently <18 years of age as of December 2024.

^a FXA, Factor XA; LMWH, Low-molecular-weight heparin. Note that the TriNetX database rounds up to the nearest 10 patients. Anticoagulants were defined as standard anticoagulants (warfarin or lmwh [including enoxaparin, dalteparin, tinzaparin, ardeparin, or danaparoid]), FXA inhibitors (rivaroxaban, apixaban, or edoxaban), and dabigatran. ^a ≤ 10 patients were prescribed andexanet alfa on the day of a relevant bleed.

Fig 2. Anticoagulant prescribing trends among pediatric patients in TriNetX (A) and CDM (B) over time from 2007 until 2023.

CDM, Clinformatics^® Data Mart Database; LMWH, low-molecular-weight heparin (includes danaparoid, tinzaparin, enoxaparin, dalteparin, and ardeparin). The data represent the proportion of patients <18 years old at the time of prescription who were being treated with each anticoagulant type, calculated as a percentage of the number of unique patients with any anticoagulant prescription, for each year. Some patients had prescriptions for > 1 anticoagulant type, so the proportions sum to over 100%. Note that TriNetX rounds values up to the nearest 10 patients.

Fig 3. Trends in pediatric FXa inhibitor prescriptions by age group in TriNetX^a (A) and CDM (B) (2013 to 2023).

CDM, Clinformatics^® Data Mart Database; FXa, factor Xa. Note that TriNetX rounds values up to the nearest 10 patients. For TriNetX, percentages may total >100% due to patient rounding and potential overlap between age groups.

Fig 4. Most common relevant bleeding events among patients prescribed FXA inhibitors (N =  890).

FXA, Factor XA; ICD-10, International Classification Of Diseases, 10th revision. A total of 890/9470 (9.4%) patients on FXA inhibitors experienced relevant bleeding events. only records comprising ≥0.5% of the total Cohort (N = 9470) are shown. All data are shown in S5 Table. ICD-10 codes were categorized as intracranial, gastrointestinal (lower and upper), or other. note that the TriNetX database rounds values up to the nearest 10 patients.