Direct oral anticoagulants for venous thromboembolism in pediatrics
A review of current guidelines in treatment and thromboprophylaxis.
Direct oral anticoagulants for venous thromboembolism in pediatrics | Image credit: © Artur - © Artur - stock.adobe.com.
Venous thromboembolism (VTE) is a rare but life-threatening condition in pediatrics, posing unique challenges in treatment and prevention within this age group. VTE incidence in pediatric patients has increased in the past decades, mostly as a complication of modern health care (eg, chemotherapy agents, central vascular catheters, major surgeries), particularly in neonates and teenagers.1
Anticoagulants are the current standard for prevention and management of VTE. Classical anticoagulants include heparin and its derivatives, low–molecular weight heparin, which act to inhibit activated factor II (prothrombin) and activated factor X (FXa) through activation of antithrombin III, and vitamin K antagonists (eg, warfarin) that block
synthesis of vitamin K–dependent coagulation factors.
Limitations of these medications include frequent laboratory monitoring, injections, unpredictable pharmacokinetics (PK), and drug and food interactions. These lead to notable anxiety and medical stress for patients and their caregivers.
Since the first direct oral anticoagulant (DOAC) was approved by the FDA in 2010 for use in adults, there have been several clinical trials to evaluate use in pediatrics. The EINSTEIN Jr (NCT02234843) and DIVERSITY trials resulted in FDA approval of rivaroxaban and dabigatran, respectively, in pediatric age groups.2-4 Use of these medications provides advantages in a younger population as they are orally administered, and based on their chemical properties and direct effect, they have more consistent PK and pharmacodynamic (PD) profiles.5
In the most recent American Society of Hematology published guidelines for the treatment of pediatric VTE in 2018, DOACs were still considered investigational in children and were not included.6 However, new guidelines are expected to be published soon and to reflect the new approvals of DOACs in pediatrics.
Here we will review the clinical pharmacology and current guidelines for the use of DOACs as treatment and prophylaxis of VTE in pediatrics. A summary table has been provided for reference (Table).
DOAC classification, mechanism of action, and clinical use
DOACs can be classified by their mechanism of action into direct FXa inhibitors (rivaroxaban, apixaban, edoxaban, all including “xa” in the drug names) and direct thrombin inhibitors (dabigatran). Of note, only rivaroxaban and dabigatran are FDA approved for use in pediatrics.
Direct FXa inhibitors act to directly inhibit free and clot-bound FXa and prothrombinase. Additionally, they indirectly inhibit thrombin-induced platelet aggregation and reduce thrombin production.
Rivaroxaban is renally excreted, and in randomized controlled trials (RCTs), it has been shown to be efficacious using scaled PK parameters compared with adults except in infants and younger children who required increased doses.7 Rivaroxaban is a substrate for CYP3A4 and P-glycoprotein, and drug-drug interactions should be evaluated prior to prescribing.8
The EINSTEIN Jr phase 3 study has provided the most compelling data for body weight–adjusted rivaroxaban tablets or oralsuspension for acute VTE in children, and findings showedlow VTE recurrence risk and reduced thromboticburden without increased bleeding.4 Furthermore, patients in this study had a greater proportion of complete thrombus resolution compared with standard of care.
Direct thrombin inhibitors can also be used for treatment of VTE and act by competitively inhibiting thrombin to prevent the conversion of fibrinogen to fibrin. Dabigatran is the only approved medication in this class and is renally excreted. Findings from phase 2 studies of dabigatran showed similar PK and PD profiles in children when dosed 80% to 100% of adult dosing for VTE treatment using the Hayton formula.9
Based on these promising results, the DIVERSITY phase 3 trials were performed to establish efficacy and safety, and findings showed favorable use of dabigatran as a high-quality and safe treatment when compared with the standard of care.2
Results were consistent with modified dosing for renal impairment and included administration with capsules and pellets, with similar observed effect when dosed appropriately for age and medication form (capsules and pellets are not bioequivalent).10,11 Dabigatran does not come in a commercially available liquid suspension, and minimum age of administration is 3 months.12 Challenges with administration continue to include complex dosing calculations and associated medication risks such as major and minor bleeding risks.
Of note, all published RCTs for DOAC use in pediatrics had insufficient power to independently demonstrate efficacy or safety in their findings.13 Additionally, their strict exclusion criteria limit use in infants with prematurity or low birth weight as well as pediatric patients with significant liver or renal dysfunction or those at high risk of bleeding. There is poor representation of racial and ethnic minority populations and patients with key comorbid conditions (eg, prosthetic heart valves), further limiting generalizability.
Though not currently approved for pediatrics, there are active clinical trials to determine safety and efficacy of apixaban and edoxaban for treatment and prophylaxis of pediatric VTE. The Hokusai VTE PEDIATRICS RCT to evaluate edoxaban for treatment and secondary prevention of VTE recently closed, and the CANINES RCT for apixaban treatment of VTE in pediatrics remains open.13,14 Apixaban is unique in that it is partially excreted through the hepatobiliary system and comes in a liquid and tablet form, though the liquid formulation cannot be dosed for those younger than 5 years.5
Thromboprophylaxis
Both dabigatran and rivaroxaban are FDA approved for secondary prophylaxis after initial therapy for VTE. Additionally, rivaroxaban is approved for primary prophylaxis in pediatric patients 2 years or older with congenital heart disease after the Fontan procedure and is dosed lower in this setting.15
Reversal agents
In cases of emergency bleeding in patients receiving anticoagulants, reversal agents are necessary to halt their effects and stop the bleeding. There are 2 FDA-approved reversal agents for use in adults: idarucizumab for reversal of dabigatran (approved in 2015) and andexanet alfa for reversal of rivaroxaban and apixaban (approved in 2018). Idarucizumab is currently being evaluated in a phase 3 trial for pediatric use; however, neither of these agents are currently approved reversal agents for use in pediatrics.16
Conclusion
In summary, trial data of DOAC use for VTE in pediatrics are limited, though current RCTs provide evidence of low incidence of recurrent VTE and major bleeding complications. Further studies are needed to answer the limitations of these trials as well as knowledge gaps in efficacy, safety, up-front VTE treatment, and use in special populations.
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References:
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