Anticoagulation in Pediatrics: DOACs on the Horizon

Jasmine Manning, PharmD Candidate 2019; Diane Nykamp, PharmD


US Pharmacist. 2019;44(5):HS8-HS12. 

In This Article

What's on the Horizon?

The advantages of DOACs include oral dosage formulations, including oral suspension; minimal laboratory monitoring; predictable pharmacokinetics; and no food interactions, making DOACs excellent options for both adults and children. However, the use of the DOACs in pediatrics is limited due to the lack of clinical trial and outcomes data to support the safety and efficacy.

Rivaroxaban: Rivaroxaban was the first FDA-approved DOAC, indicated for adults with nonvalvular atrial fibrillation, treatment and prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of DVT in patients who underwent knee or hip replacement. Rivaroxaban is a once-daily oral agent that has minimal drug interactions, high bioavailability, and minimal monitoring requirements, making it an ideal anticoagulant for the potential use in pediatrics. EINSTEIN Junior is a phase III randomized controlled trial evaluating the comparative safety and efficacy of rivaroxaban and standard therapy in children for acute VTE.[8] The study population includes children aged 6 months to less than 18 years initiated and treated with UFH, LMWH, or fondaparinux who require anticoagulant therapy for at least 90 days. Unlike the standard adult dosing of 20 mg daily, the pediatric dose of rivaroxaban can range from 0.8 mg/kg/day to 1.2 mg/kg/day and be adjusted to obtain blood levels equivalent to the adult 20-mg dose.[8] Patients aged 12 to 18 years received 20 mg daily, while patients aged 6 months to less than 12 years received an adjusted oral suspension dose equivalent to 20 mg in adults. The estimated study completion date is during the first quarter of 2019.[8]

Apixaban: Apixaban, like rivaroxaban, is FDA approved for adults for treatment of DVT and PE, nonvalvular atrial fibrillation, and prevention of DVT in postoperative hip or knee replacement. Apixaban is like rivaroxaban with regard to its advantages and disadvantages; however, oral apixaban requires twice-a-day dosing, unlike rivaroxaban. To date there is one phase III and one phase IV trial underway evaluating the safety and efficacy of apixaban in pediatric patients. The phase III trial compares the effect of administering apixaban versus no administration of a blood-thinning drug in preventing blood clots in children with leukemia or lymphoma. Patients must be receiving chemotherapy, including asparaginase, and have a central-line catheter to participate in the study.[9] Patients weighing less than 35 kg will receive a fixed dose based on body weight twice a day for 28 days; patients weighing more than 35 kg will receive 2.5 mg twice a day for 28 days. The primary efficacy endpoint is a composite of nonfatal DVT/PE, cerebral venous sinus thrombosis, and VTE-related death up to 1 month after therapy.[9] The phase IV trial is an open-label study, assessing the safety and efficacy of apixaban in pediatric subjects requiring anticoagulation for the treatment of a VTE.[10]Patients will receive either standard therapy or apixaban doses based on a set body-weight tiered regimen. Participants weighing 35 kg or more will receive 10 mg twice daily for 7 days followed by 5 mg twice daily. Those weighing less than 35 kg will be dosed according to a tiered dosing schedule.10 The estimated study completion dates for the phase III trial are May 2020 and April 2021 for the phase IV trial.[9,10]

Edoxaban: Edoxaban, an Xa inhibitor, was approved by the FDA in 2015 for adults for treatment of DVT/PE and nonvalvular atrial fibrillation. Edoxaban can be used at a reduced dose in patients with a creatinine clearance (CrCl) range of 15–50 mL/min, which is an advantage when compared with apixaban and riva-roxaban, where safety and efficacy in patients with CrCl <30 mL/min have not been studied. However, edoxaban has a black box warning for avoiding use in patients with CrCl >95 mL/min because of the ENGAGE AF TIMI study results, in which patients with nonvalvular atrial fibrillation had an increased rate of ischemic stroke with edoxaban 60 mg once daily compared with those treated with warfarin.[11] Clinicians should assess renal function prior to deciding to initiate therapy, as the correlation between this dose and renal function is not clearly understood in adult patients. To date, one phase III trial is underway, evaluating the pharmacokinetics and pharmacodynamics of edoxaban and comparing the efficacy and safety of edoxaban against standard of care in pediatric subjects with confirmed VTE. Patients aged 12 to 18 years will receive 15-mg or 30-mg tablets and patients under 12 years of age will be dosed according to body-weight regimen with a suspension.12 The estimated study completion date for the phase III trial is March 2021.[12]

Dabigatran: Dabigatran is a direct thrombin inhibitor approved for DVT/PE treatment and nonvalvular atrial fibrillation in adults. As with the Xa inhibitors, there is no therapeutic drug monitoring required, making it an ideal option for pediatric patients. Maas and colleagues completed a study evaluating the effect of age on the relationship between plasma dabigatran concentration and standard coagulation assay results, which may help determine the most appropriate assay for pediatric use. The results of the study suggest that the development of the clotting system in children will have little impact on response to dabigatran.[13] There are currently two phase III trials evaluating the use of dabigatran as treatment and prevention options. The first trial is assessing the efficacy and safety of dabigatran compared with standard-of-care and documenting the appropriateness of the protocol-proposed dabigatran dosing algorithm for use in patients from birth to age less than 18 years.[14] The second phase III trial is evaluating the safety of dabigatran in secondary prevention of VTE in pediatric patients. Participants must have completed a course of initial VTE treatment prior to enrollment.[15] Both trials will use an age- and weight-appropriate capsule dose (combination of 50-mg, 75-mg, and 110-mg capsules), pellets, or oral liquid formulation in the dosing algorithm.1[4,15] The estimated completion date for both trials is February 2020.[14,15]

There are currently FDA-approved reversal agents for apixaban, rivaroxaban, and dabigatran. However, owing to a lack of efficacy and safety data, these reversal agents are not currently approved for use in pediatrics. Idarucizumab is a humanized monoclonal antibody that specifically binds to dabigatran and its active metabolite.[16] Idarucizumab is the only FDA-approved agent for reversing the anticoagulant effect of dabigatran for emergency surgery or urgent procedures, or in the event of life-threatening or uncontrolled bleeding in adults. Andexanet alfa is a recombinant modified human factor Xa decoy protein that binds and sequesters the Xa inhibitors rivaroxaban and apixaban.[17] Andexanet alfa is the only FDA-approved agent for reversing the anticoagulation in adult patients treated with apixaban or rivaroxaban who are experiencing life-threatening or uncontrolled bleeding.[17]

Aripazine (Corporates, PER977), an investigational agent, is a small molecule and is a nonspecific antidote for all DOACs and heparins. Aripazine is being studied in clinical trials, with phase II trial data reported that has found the reversing anticoagulant effects to occur within 30 minutes of an IV bolus administration.[18] Reversal-agent studies to date examining safety and efficacy within the pediatric population are lacking.