To learn or not to learn from real-world experience on direct oral anticoagulants in pediatric patients?

In the recent issue of Research and Practice in Thrombosis and Hemostasis, Corrales-Medina et al. [1] reported on the clinical experience with direct oral anticoagulants (DOACs) in 233 children treated across 15 centers from the United States (US). Contributing centers are a part of the American Thrombosis and Hemostasis Network (ATHN), which is an active network that continuously provides important clinical information. [2] The authors conclude that DOACs show adequate safety and effectiveness rates compared with standard therapy. However, two questions arise: (1) is this conclusion justified? and (2) what is the value of this clinical observation, compared with the results from rigorously planned and executed clinical trials?

It has to be kept in mind that DOACs overcome many limitations of standard anticoagulant therapy in pediatric patients: they are administered orally (including liquid formulation), are antithrombin independent, have a rapid onset and offset of action, and have predictable pharmacokinetics with a limited need of laboratory monitoring for plasma levels and anticoagulant activity. As DOACs are increasingly used in pediatric patients, it is of utmost importance to be mindful of their specific limitations in these patients and conceivable differences between individual DOACs. [3,4] DOACs are the first generation of anticoagulants that are thoroughly investigated according to a formal pediatric investigation plan. Rivaroxaban and dabigatran have already been approved by the European Medicine Agency and the US Food and Drug Administration for the treatment of pediatric venous thromboembolism (VTE). [5,6,7] There are ongoing clinical trials to evaluate apixaban and edoxaban in pediatric patients. So far, study results are encouraging for all DOACs when compared with standard of care.

This cohort of 233 children and adolescents from 15 US centers is certainly a good source of clinical information to provide additional safety data. It aptly represents the spectrum of pediatric patients primarily treated with DOACs at present. After gaining more experience, DOACs might be more often used in pediatric patients weighing <10 kg and under one year of age. Although Corrales-Medina et al. [1] included some young patients (3.4%, <30 kg; 9.9%, <13 years), the numbers were too low to make any firm conclusions.

DOACs are also increasingly prescribed in pediatric patients with complex disorders who are under multimodal therapy, often with polypharmacy. In these patients, VTE is a frequent complication that may delay or even prevent recovery. Many of these pediatric patients did not meet clinical trial inclusion criteria but were included by Corrales-Medina et al. [1] in their report.

It is of interest that the median age of investigated pediatric patients was 16.5 years with 53.6% girls and women. Overall, 31% of the participants reported bleeding complications on DOACs, with major or clinically relevant nonmajor bleeding in 0.4% and 0.9% of the participants, respectively. DOAC-related heavy menstrual bleeding was observed in 35.7% of female patients (>12 years). As most of the participants received rivaroxaban or apixaban (98%), the differences in heavy menstrual bleeding between these two drugs became obvious, with 45.6% and 18.9% in the rivaroxaban and the apixaban-treated group, respectively (P = .004 using the chi-squared test). Does this mean that one drug induces more menstrual bleeding than the other? Yes; however, this needs further evaluation. Owing to the retrospective and prospective data collection, conclusions must be drawn with caution. Epistaxis, heavy menstrual bleeding, and other mucosal bleeding are commonly reported side effects in pediatric patients undergoing DOAC therapy. Preliminary results from an international DOAC registry confirm a relatively higher bleeding frequency with DOACs compared with standard of care in pediatric patients. [8] Other clinical side effects were not observed.

Recurrence of thrombosis occurred in 4% of pediatric patients in a 6-month follow-up period. Local recurrence of VTE occurred nearly as frequently as recurrence at another location. Participants were treated with different anticoagulants and dose regimens. Therefore, recurrence could not clearly be attributed to a specific DOAC treatment. Controlled clinical studies show similar recurrence rates, eg, the EINSTEIN-Jr trial showed a recurrence rate of 1% after treatment with rivaroxaban compared with 3% with standard anticoagulants (hazard ratio, 0.4; 95% CI, 0.11-1.41). [5]

Taken together, the authors’ conclusions concerning safety and effectiveness of DOACs agree with available results from the two published randomized, controlled clinical studies comparing DOACs with standard anticoagulant therapies. [5,7] Thus, rivaroxaban and apixaban appear to be safe alternatives to standard of care with heparin and vitamin K antagonists in older children.

But what do we really learn from this data collection from 15 specialized centers? Already in 2015, specialists of the ATHN used DOACs off-label in selected pediatric patients. Rivaroxaban and apixaban, both potent Xa-inhibitors, were preferred over the thrombin inhibitor dabigatran. Corrales-Medina et al. [1] gave several plausible explanations including the local availability, experience from clinical trial participation, DOAC dosage, and formulation (liquid vs tablet). It is obvious that ATHN investigators searched for data on a new generation of anticoagulants with preferable properties compared with heparin and vitamin K antagonists (Figure) [9]. Fortunately, participants in the ATHN showed a very pleasing adherence to DOAC therapy, though usually, adherence to therapies is much better in clinical trials than in real life.

Figure.

Venous thromboembolism (VTE) is an increasingly recognized and important hospital-acquired complication in pediatric patients [9]. Direct oral anticoagulants (DOACs) are a new class of anticoagulants for the management of VTE in pediatric patients, which has the potential to largely replace parenteral standard anticoagulants. The photomicrograph shows a human blood clot visualized via Real Time Live Confocal Imaging visualizing the fibrin network (green, ffbp), platelet aggregates (yellow due to WGA and ffbp overlay), and erythrocytes (red, WGA). Objective: 63× oil immersion merged confocal image of whole blood clot formation. CVC-VTE, central venous catheter-related VTE; CVST, cerebral venous and sinus thrombosis; WGA, wheat germ agglutinin

Due to the relative rarity of VTE in pediatric patients, most likely, one DOAC of choice will be preferred in each institution. Thus, comparable data on all different DOACs might not be available in the near future, neither from real-life data nor from prospective clinical studies. This fact increases the risk that it will take a long time to recognize differences between DOACs in different age groups and clinical settings.

Overall, many questions are still open and left for further research:

• -Is immediate starting of DOACs without preceding heparin therapy in pediatric patients reasonable? Are higher starting doses necessary? Do DOACs positively influence prevention of postthrombotic syndrome?
• -Are DOACs safe and effective for very young patients? Are they safe and effective in the presence of polypharmacy?
• -Mucosal bleeding, including epistaxis and heavy menstrual bleeding, is frequently reported. Are there any differences, in terms of bleeding, between available DOACs?
• -What is the availability of bridging and periprocedural protocols? So far, guidelines are only extrapolated from experiences in adult patients.
• -What are the pharmacokinetics and -dynamics of DOAC reversal agents?

There is a paucity of evidence to guide the real-world use of DOACs in pediatric patients for prevention and treatment of VTE. Clinical observations are very important to further accompany and supplement findings from well-designed clinical studies, as they reflect clinical practice and experience. A growing body of evidence from all sources will be best for treating pediatric patients with VTE and guiding their caregivers.

Relationship Disclosure

There are no competing interests to disclose.