What new evidence is available to support the use of direct oral anticoagulants (DOACs) in pediatric patients for venous thromboembolism (VTE) treatment and prevention?

Introduction
Venous thromboembolism (VTE) occurs rarely in pediatric patients, with an overall incidence estimated to be 0.07 to 0.49 per 10,000 children,1 compared to an annual incidence in adults of about 1 per 1000.2 The pathophysiology of VTE and optimal treatment and prevention strategies in children is still not completely known due to the scarcity of events in this population.3 Current guidelines for management of VTE in the pediatric population recommend use of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux, or vitamin K antagonists for anticoagulation based on available safety and efficacy data.3,4 Since the publication of these guidelines, clinical and pharmacokinetic trials have demonstrated safety and efficacy of rivaroxaban and dabigatran, direct oral anticoagulants (DOACs), in pediatric patients.5-8 In 2021, the US Food and Drug Administration (FDA) approved dabigatran and rivaroxaban for the treatment of VTE and reduction in risk of recurrent VTE in pediatric patients, based on clinical trial data and data extrapolated from adult trials.9-11 This article will discuss the efficacy and safety of recently approved agents, rivaroxaban and dabigatran, in the pediatric population.

Background
Rates of VTE are notably higher in hospitalized children, with an estimated incidence of 4.9 to 21.9 per 10,000 hospital admissions.1 The majority of thromboembolic events in pediatric patients are provoked with an identifiable cause and less than 5% are idiopathic.12 Notable risk factors for VTE in pediatric patients include the presence of central venous access devices, intensive care unit stays, mechanical ventilation, malignancy, and length of hospital stay.1,3,4,12,13 One study found that the incidence of hospital-acquired VTE has increased from 0.3 to 28.8 cases per 10,000 admissions from 1992 to 2005, while another study found an increase from 34 to 58 cases per 10,000 admissions between 2001 and 2007.1 The increasing incidence of VTE in pediatric patients is thought to be due to longer life expectancy of children with chronic medical conditions who are inherently at a higher risk for VTE events, making appropriate anticoagulation for management of VTE and reduced risk of recurrence even more critically needed.12,13

Current standard of care
The current pediatric VTE treatment guidelines, including the 2012 guidelines on antithrombotic therapy and prevention of thrombosis in neonates and children from the American College of Chest Physicians and the 2018 American Society of Hematology pediatric VTE guidelines, recommend UFH, LMWH, or vitamin K antagonists, such as warfarin, for anticoagulation treatment of VTE in children.3,4 Many of these pediatric treatment recommendations are extrapolated from adult data due to the lack of available data in children and adolescents. Similar to adults, warfarin and parenteral anticoagulation (UFH, LMWH) require diligent and regular monitoring in children. Therapeutic levels for International Normalized Ratio (INR) for warfarin and anti-Xa levels or activated partial thromboplastin time for parenteral anticoagulants in pediatric patients are extrapolated from adult data. Dose adjustments may be required to achieve therapeutic drug concentrations, providing challenges with adherence and administration.

Guidelines on antithrombotic therapy in adults recommend DOAC agents, apixaban, dabigatran, edoxaban, and rivaroxaban, as first-line VTE treatment.14,15 The American Society of Hematology 2018 guidelines state that DOAC agents did not have established pharmacokinetic, safety, or efficacy studies at the time of their guideline publication, so they did not recommend these agents in children outside of clinical trials.3 With the recent approvals of rivaroxaban and dabigatran in pediatric patients, forthcoming guideline updates will likely adapt their recommendations to include these agents. There are many potential benefits to DOAC therapy over conventional anticoagulation therapy. No routine monitoring is required with DOAC agents, which may be beneficial in individuals who are non-compliant with current regimens.9-11 No dietary considerations are necessary when dosing DOAC agents. In comparative trials, DOAC agents have been associated with a lower risk of bleeding compared to warfarin and parenteral agents.

Switching patients from vitamin K antagonists or parenteral anticoagulants to a DOAC requires consideration. The goal is to maintain therapeutic anticoagulation throughout the transition. See Table 1 for guidance on appropriate transitions in pediatric patients.

Table 1. Transitioning anticoagulation to a DOAC in pediatric patients.9-11
DOAC Converting from warfarinConverting from parenteral anticoagulants
DabigatranDiscontinue warfarin and initiate dabigatran when INR <2
Start DOAC 0 to 2 hours prior to the next scheduled administration of LMWH or non-warfarin oral anticoagulant and omit administration of the other anticoagulant.

For UFH being administered continuously, stop the infusion and initiate DOAC at the time of discontinuation.
Rivaroxaban
Discontinue warfarin and initiate rivaroxaban when INR<2.5
Abbreviations: DOAC=direct oral anticoagulant; INR=international normalized ratio; LMWH=low molecular weight heparin; UFH=unfractionated heparin

Recent approvals
In 2021, the FDA approved 2 DOACs, dabigatran and rivaroxaban, for the treatment of VTE and reduction in risk of recurrent VTE in pediatric patients.9-11 Rivaroxaban also received approval for thromboprophylaxis in pediatric patients with congenital heart disease after Fontan procedure.11 Rivaroxaban is a selective inhibitor of factor Xa. Rivaroxaban suspension is indicated for patients weighing less than 30 kg and is dosed according to patient’s weight. In patients weighing greater than 30 kg, patients may take the suspension or tablets. Dabigatran is a competitive direct thrombin inhibitor.9,10 Dabigatran is dosed in pediatric patients based on age and weight. Routine laboratory monitoring is not recommended for either of these medications.9-11 Trials evaluating the efficacy of rivaroxaban and dabigatran for the treatment of VTE in pediatric patients can be found in Table 2.

Efficacy
The trials listed in Table 2 support the approvals of rivaroxaban and dabigatran for treatment of VTE in the pediatric population. Rivaroxaban approval is supported by the Male et al 2020 and McCrindle et al 2021 trials.5,6 The Male et al 2020 trial was not powered to demonstrate non-inferiority, so it relied on adult studies for extrapolation of similar rates of VTE.5,16 The McCrindle et al 2021 trial was also not powered to detect a statistically significant difference; however, it did find less thromboembolic events with rivaroxaban compared to aspirin.6 Pediatric approval for dabigatran is supported by the Halton et al (2021) and Brandão et al (2020) trials.7,8 In the Halton et al trial, the rates of VTE for pediatric patients on dabigatran were similar to rates of VTE on dabigatran in adult trials.7,17 The Brandão et al trial was limited by its open-label design, but the study demonstrated that children treated with dabigatran for secondary VTE prevention had a low risk of VTE recurrence.8

Table 2. Literature for efficacy of DOAC use in pediatric patients.5-8
Study design and durationSubjectsInterventionsResults
Conclusions
Rivaroxaban
Male 20205

MC, OL RCT

Median follow up 91 days (n=463) or 31 days (n=37), based on age		N=500 children between 0 and 17 years old with confirmed VTE and started on heparinRandomized 2:1 ratio to receive OL rivaroxaban (body weight-adjusted 20-mg equivalent dose) or standard anticoagulation (continued heparin or switched to vitamin K antagonist) for 3 monthsSymptomatic recurrent VTE occurred in 4 (1%) children in the rivaroxaban group vs 5 (3%) children in standard anticoagulation group (HR, 0.40; 95% CI, 0.11 to 1.41)

Complete resolution of the original thrombosis occurred in 128 (38%) children in the rivaroxaban group vs 43 (26%) children in the standard anticoagulation group (OR, 1.70; 95% CI, 1.11 to 2.58; p=0.012)


Clinically relevant bleeding events were similar between groups (3% in rivaroxaban group vs 2% in standard anticoagulation group; HR, 1.58; 95% CI, 0.51 to 6.27)

The composite of recurrent VTE or major bleeding occurred in 4 (1%) children in the rivaroxaban group vs 7 (4%) in standard anticoagulation group (HR, 0.30; 95% CI, 0.08 to 0.93)


Although this trial was not powered to demonstrate non-inferiority, treatment with rivaroxaban resulted in a reduced risk of composite recurrent VTE or major bleeding compared to standard anticoagulation. However, clinically relevant bleeding was not significantly different between groups.
McCrindle 20216

MC, 2-part, OL RCT

Study duration: 12 months		N=112 children 2 to 8 years old with single-ventricle congenital heart disease who had undergone a Fontan procedure within 4 months before enrollment and required thromboprophylaxis

Part A was a single-arm PK and PD study (n=12)

Part B was main efficacy and safety study (n=100)		Randomized 2:1 ratio to receive rivaroxaban (body weight-adjusted 10-mg equivalent) vs aspirin ~5 mg/kg per dose for 12 monthsAny thrombotic event (venous or arterial) occurred in 1 patient on rivaroxaban (Part B) and 3 patients on aspirin (overall event rate: 2% vs 9%, respectively; risk difference, -7.3%; 95% CI, -21.7% to 1.1%)Although this study was not powered for efficacy hypothesis testing, treatment with rivaroxaban resulted in fewer thrombotic events (although not statistically significant) and a similar safety profile compared to aspirin.
Dabigatran
Halton 20217

MC, OL, non-inferiority RCT

Follow-up duration: 3 months		N=267 children <18 years old who were diagnosed with acute VTE and treated with parenteral anticoagulation for 5 to 21 daysRandomized 2:1 ratio on dabigatran (weight and age adjusted dosing) vs standard of care (LMWH, UFH, vitamin K antagonist or fondaparinux) for 3 monthsComposite outcome of proportion of children with complete thrombus resolution and freedom from recurrent VTE and VTE-related death was achieved in 42% of patients treated with standard of care and 46% of patients treated with dabigatran (difference, –0.04; 90% CI, -0.04 to 0.07; p<0.0001 for non-inferiority)Dabigatran was found to be non-inferior to standard of care (LMWH, UFH, vitamin K antagonist, or fondaparinux) for VTE treatment in children. Overall bleeding and major bleeding were similar between groups.
Brandão 20208
Prospective, OL, single arm, cohort trial

Follow-up duration: 12 months		N=203 children 3 months to <18 years old with an objectively confirmed diagnosis of VTE treated with standard of care for 3 months or longer or had completed dabigatran or standard of care treatment in the DIVERSITY trial and had an unresolved clinical thrombosis risk factor requiring continued anticoagulationChildren received dabigatran (weight and age adjusted dosing) for up to 12 monthsOverall, 2 children (1%) experienced recurrence of VTE: 1 child within 3 months of treatment and the other within 6 months of treatment

The probability of freedom from recurrent VTE at 12 months across all age groups during the treatment period was 0.988 (95% CI, 0.951 to 0.997)		In children treated for secondary VTE prevention with dabigatran, there is a low risk of VTE recurrence
Abbreviations: CI=confidence interval; DOAC=direct oral anticoagulants; HR=hazard ratio; LMWH=low-molecular weight heparin; MC=multicenter; OL=open-label; OR=odds ratio; PD=pharmacodynamic; PK=pharmacokinetic; RCT=randomized-controlled trial; UFH=unfractionated heparin; VTE= venous thromboembolism.

Safety
Rivaroxaban
In pediatric clinical trials, rivaroxaban was found to have a similar safety profile compared to other anticoagulation strategies. In the Male et al trial, major or clinically relevant non-major bleeding events were not significantly different compared to standard of care (3% vs 2%; hazard ratio [HR], 1.58; 95% confidence interval [CI], 0.51 to 6.27).5 However, the composite outcome of symptomatic recurrent VTE or major bleeding occurred in significantly fewer children in the rivaroxaban group compared to the standard anticoagulation group (1% vs 4%; HR, 0.3; 95% CI, 0.08 to 0.93). In the McCrindle et al trial, there was 1 child with a major bleeding event in the rivaroxaban group requiring a blood transfusion and no major bleeding events in the aspirin group.6 Clinically relevant nonmajor bleeding events occurred more frequently in the aspirin group (9%) compared to the rivaroxaban group (6%). Adverse events were similar in both groups.

Rivaroxaban carries a boxed warning including increased risk of thromboembolic events with premature discontinuation and spinal or epidural hematomas in patients on rivaroxaban receiving neuraxial anesthesia or undergoing spinal puncture. 11 When starting rivaroxaban, the risk versus benefit should be considered. Use is not recommended in individuals with prosthetic heart valves, triple positive antiphospholipid syndrome, or those with active bleeding. Additional warnings include increased risk of bleeding. Concomitant medications that may increase the risk of bleeding include antiplatelets, antithrombotic agents, fibrinolytics, non-steroidal anti-inflammatory agents, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. Concomitant use of medications that are P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) inhibitors increase the risk of bleeding. The most common adverse reactions (>10%) in pediatric patients include bleeding, cough, vomiting, and gastroenteritis.

Dabigatran
In the Halton et al trial, any bleeding event occurred in 24% of children receiving standard of care and 22% of children receiving dabigatran (HR, 1.15; 95% CI, 0.68 to 1.94; p=0.61).7 The proportion of children having major bleeding events was the same for standard of care (2%) and dabigatran (2%). Headache, vomiting, and abdominal pain were the most reported adverse events. In the cohort trial by Brandão et al, dabigatran resulted in a total of 40 (19.7%) bleeding events, the majority of which were considered minor (18.2%).8 The most common adverse events reported included nasopharyngitis, headache, and abdominal pain.

Similar to rivaroxaban, dabigatran carries a boxed warning for increased thrombotic risk with abrupt discontinuation and spinal or epidural hematoma.9,10 Dabigatran is contraindicated in patients with a mechanical prosthetic heart valve and with active bleeding and use is not recommended in individuals with bioprosthetic heart valves or with triple-positive antiphospholipid syndrome. Dabigatran is associated with an increased risk of bleeding. Dabigatran use with P-gp inducers reduces exposure to dabigatran and should be avoided. The concomitant use of P-gp inhibitors in pediatric patients has not been studied, but may increase exposure to dabigatran, increasing bleed risk.

Conclusion
Recent clinical trial data on the use of rivaroxaban and dabigatran for the treatment of VTE and reduction of recurrent VTE in pediatric patients has led to new FDA approvals. Rivaroxaban received FDA approval for 2 pediatric indications in December 2021: treatment of VTE and reduction in the risk of recurrent VTE in pediatric patients from birth to18 years of age, and thromboprophylaxis in pediatric patients 2 years and older with congenital heart disease after the Fontan procedure.11 In June 2021, dabigatran pellets received FDA approval for VTE treatment and reduction in the risk of VTE recurrence in patients aged 3 months to less than 12 years and dabigatran capsules received the same indications for patients aged 8 to less than 18 years.9,10 The most recent pediatric anticoagulation guidelines were published prior to the approvals of dabigatran and rivaroxaban.3,4 While DOACs continue to be studied, they appear to be safe and effective in the pediatric population. Benefits of DOACs over traditional anticoagulation include no laboratory monitoring requirements, similar bleeding risk, and increased efficacy. Additional studies on the use of apixaban and edoxaban are ongoing in pediatric patients.18,19

References

  1. Mahajerin A, Croteau SE. Epidemiology and risk assessment of pediatric venous thromboembolism. Front Pediatr. 2017;5:68. doi: 10.3389/fped.2017.00068
  2. Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol. 2007;44(2):62-69. doi: 10.1053/j.seminhematol.2007.02.004
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  5. Male C, Lensing AWA, Palumbo JS, et al. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematol. 2020;7(1):e18-e27. doi: 10.1016/S2352-3026(19)30219-4
  6. McCrindle BW, Michelson AD, Van Bergen AH, et al. Thromboprophylaxis for children post-Fontan procedure: insights from the UNIVERSE Study. J Am Heart Assoc. 2021;10(22):e021765. doi: 10.1161/JAHA.120.021765
  7. Halton J, Brandão LR, Luciani M, et al. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial. Lancet Haematol. 2021;8(1):e22-e33. doi: 10.1016/S2352-3026(20)30368-9
  8. Brandão LR, Albisetti M, Halton J, et al. Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children. Blood. 2020;135(7):491-504. doi: 10.1182/blood.2019000998
  9. Pradaxa oral pellets. Package insert. Boehringer Ingelheim Pharmaceuticals; 2021.
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  11. Xarelto. Package insert. Janssen Pharmaceutical Companies; 2021.
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  13. Mahajerin A, Branchford BR, Amankwah EK, et. al. Hospital-associated venous thromboembolism in pediatrics: a systematic review and meta-analysis of risk factors and risk-assessment models. Haematologica. 2015;100:1045-1050. doi: 10.3324/haematol.2015.123455
  14. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report. Chest. 2021;160(6):e545-e608. doi: 10.1016/j.chest.2021.07.055
  15. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257-3291. doi: 10.1182/bloodadvances.2018024893
  16. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. doi: 10.1056/NEJMoa1007903
  17. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352. doi: 10.1056/NEJMoa0906598
  18. Apixaban for the acute treatment of venous thromboembolism in children. Clinicaltrials.gov. Accessed March 3, 2022. https://clinicaltrials.gov/ct2/show/NCT02464969
  19. Hokusai study in pediatric patients with confirmed venous thromboembolism (VTE). gov. Updated January 10, 2022. Accessed March 3, 2022. https://clinicaltrials.gov/ct2/show/NCT02464969

Prepared by:
Justyna Fydrych, PharmD
PGY1 Pharmacy Practice Resident
John H. Stroger, Jr. Hospital of Cook County

Rachel Brunner, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2022

The information presented is current as February 28, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.