Direct oral anticoagulants in pediatric venous thromboembolism: Experience in specialized pediatric hemostasis centers in the United States
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Design
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Multi-center, retrospective and prospective cohort, chart review
N= 233
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Objective
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To investigate the use of direct oral anticoagulants (DOACs) at 15 different American Hemostasis and Thrombosis Network (ATHN)-affiliated specialized pediatric hemostasis centers with an emphasis on safety and effectiveness
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Study Groups
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ATHN 15 patients (N= 233)
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Inclusion Criteria
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Patients aged 0 to 21 years at the time of DOAC treatment for anticoagulation management of acute venous thromboembolism (VTE) or secondary prevention of VTE
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Exclusion Criteria
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Did not sign informed consent or provide authorization for ATHNdataset network inclusion
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Methods
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The ATHNdataset was reviewed for study participants and divided into two cohorts. The retrospective cohort included patients who completed DOAC treatment ≥6 months before study enrollment, with the prospective cohort including patients who started a DOAC at the time of enrollment. Analyzed data consisted of demographic characteristics, baseline medical history, and use of hormonal therapy (use of any combined estrogen and progestin oral or transdermal contraceptives within 4 weeks before VTE onset). Identification of congenital thrombophilia conditions was based upon cutoff determination values of reported protein C, protein S, and antithrombin deficiencies set at the investigator's discretion.
Treatment-related bleeding events were classified as major, clinically relevant nonmajor bleeding (CRNMB), or minor. Major bleeding consisted of fatal, clinically overt (hemoglobin ≥2 mg/dL within 24 hours and/or bleeding was retroperitoneal, pulmonary, intracranial, or central nervous system), or required surgical intervention. CRNMB consisted of any overt bleeding required blood product, not attributed to patient's underlying condition, and required medical or surgical intervention, to restore hemostasis, administered other than in an operating room. Heavy menstrual bleeding (HMB) was also reported for females aged >12 years.
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Duration
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Enrollment: January 2015 to June 2021
Follow-up: 3 and 6 months post-DOAC initiation
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Outcome Measures
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VTE progression and recurrence, treatment-related bleeding, and mortality status
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Baseline Characteristics
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ATHN 15 patients (N= 233)
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Patient age at start of DOAC therapy
0 to <13
13 to <18
18 to 21
Unknown
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23 (9.9%)
164 (70.4%)
45 (19.3%)
1 (0.4%)
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Female
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125 (53.6%) |
White
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164 (70.4%) |
No prior history of thrombosis
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194 (83.6%) |
Medical risk factor(s) present at VTE diagnosis
Antiphospholipid syndrome
Autoimmune disorder
Cancer
Recent hospital admission (>7 days within 30 days before VTE)
Obesity
Trauma (within 30 days before VTE requiring casting or ICU admission)
Sepsis (within 7 days before VTE)
Other∗
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6 (2.6%)
12 (5.2%)
9 (3.9%)
263 (11.2%)
53 (22.7%)
15 (6.4%)
8 (3.4%)
47 (20.2%)
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Thrombophilia condition present at VTE diagnosis
Antithrombin deficiency
Factor V Leiden mutation (heterozygous)
Factor V Leiden mutation (homozygous)
Protein C deficiency
Protein S deficiency
Prothrombin G20210A mutation (heterozygous)
Other
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6 (2.6%)
22 (9.4%)
4 (1.7%)
13 (5.6%)
12 (5.2%)
11 (4.7%)
3 (1.3%)
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Initially prescribed DOAC
Apixaban
Dabigatran
Edoxaban
Rivaroxaban
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90 (38.8%)
3 (1.3%)
2 (0.9%)
137 (59.1%)
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Initiated on ≥1 standard anticoagulant and/or thrombolytic therapy
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203 (87.5%)
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∗Includes congenital heart disease, COVID-19/SARS-CoV-2, inborn errors of metabolism/mitochondrial disease, inflammatory bowel disease, nephrotic syndrome, pregnancy, sickle cell disease, and others.
ICU, intensive care unit
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Results
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Endpoint
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ATHN 15 patients (N= 225)†
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Thrombosis recurrence‡
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9 (4%) |
Patients with bleeding events
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31 (13.8%) |
Type of reported bleeding events
Minor
CRNMB
Major
Minor and CRNMB
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n= 31
25 (80.6%)
2 (6.5%)
1 (3.2%)
3 (9.7%)
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†Among the total 233 patients enrolled in this study, 225 completed at least 1 follow-up form.
‡No patients reporting thrombosis recurrence had previously reported congenital thrombophilia diagnosis.
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Adverse Events
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Common Adverse Events: epistaxis and reproductive tract bleeding; HMB associated with DOAC use was seen in 35 of 98 (35.7%) eligible females overall, with apixaban use in 7 patients (18.9%) and rivaroxaban use in 26 patients (45.6%)
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Serious Adverse Events: One patient receiving apixaban had a major bleeding event of the gastrointestinal tract, but resumed DOAC therapy 48 hours following resolution of bleeding with no additional complications.
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Percentage that Discontinued due to Adverse Events: A total of 15 (6.7%) patients discontinued DOAC therapy due to treatment-related bleeding events, with 8 patients restarting DOAC therapy without further bleeding complications.
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Study Author Conclusions
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Pediatric hematologists at specialized hemostasis centers in the United States have been using DOACs for the treatment and prevention of VTEs, primarily in adolescents and young adults. Reported DOAC use showed adequate safety and effectiveness rates.
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InpharmD Researcher Critique
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Study limitations include a retrospective lens, which is reliant upon accurate reporting of outcomes such a minor bleeding in patient chart, as well as study participants only from ATHN-affiliated specialized sites with higher levels of expertise in pediatric VTE management present, limiting generalizability. No subgroup analyses evaluated DOAC use for safety and efficacy outcomes in patients with factor V Leiden mutations.
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