US Pharm. 2019;44(5)HS-8-HS-12.
ABSTRACT: Pediatric anticoagulation includes the standard therapy of warfarin, unfractionated heparin, and low molecular weight heparin. Anticoagulants are used in pediatrics, but there are limited data surrounding safety and efficacy. Although venous thrombosis is more common in adults, it also occurs in children and is usually due to the use of a central venous catheter during hospitalization. An increased incidence of venous thrombosis in pediatric patients warrants the need for more favorable therapies. Several pediatric trials are currently focusing on the use of direct oral anticoagulation therapy, with a likely shift to its use in the future.
Traditionally, anticoagulants in the pediatric population have been indicated for the management of congenital heart defects, Kawasaki disease, and deficiencies of natural anticoagulants. Data have shown a steady increase in the use of anticoagulants for treatment of venous thrombosis (VTE) in pediatric patients, most commonly due to hospitalization (HA-VTE).1 The most common cause of HA-VTE is an indwelling central venous catheter.1 Catheter occlusions are due in part to venous stasis, hypercoagulability, and trauma to the vessel wall. The size of the catheter presents an additional problem since children have small vessel size and may require a large-diameter catheter. Data show that HA-VTE has increased from 5.3 events per 10,000 pediatric hospital admissions in the early 1990s to a current estimate of 30 to 58 events per 10,000 pediatric hospital admissions as of 2016.1
The rationale and approach to anticoagulation therapy in pediatrics is much like that in the adult population, but there are unique factors to consider with pediatrics. One area of concern is initiation of therapy in pediatric patients aged less than 1 year who have not fully developed the coagulation proteins needed for certain anticoagulants to take effect.2 The 2012 American College of Chest Physicians guidelines for antithrombotic therapy in neonates and children outline initiation of anticoagulant therapy with warfarin, unfractionated heparin, and low molecular weight heparin (LMWH). However, many of the dosage recommendations and the length of therapy are based on low-grade evidence.3,4 Other considerations include route of administration, drug-drug interactions, and drug-dietary interactions.4
To effectively and safely manage patients on warfarin or heparin, many institutions have developed pharmacy-driven protocols for inpatients and outpatients, allowing trained pharmacists to work collaboratively with physicians in monitoring and adjusting anticoagulant dosages. These protocols guide clinical decision-making when selecting the most appropriate anticoagulant regimen. There are several clinical trials currently underway evaluating the safety and efficacy of direct oral anticoagulants (DOACS) in pediatrics, namely, rivaroxaban and apixaban. Guidelines for pediatric DOAC use have not yet been published. If clinicians decide to initiate DOAC therapy, the benefit must outweigh the risk. Until the results of studies or updated guidelines are published, institutions will continue to use standard anticoagulant treatment protocols specific to their patient population. This article reviews standard therapy and discusses information from the current ongoing clinical studies using the DOACs.
Warfarin: Warfarin is an oral anticoagulant that acts as a vitamin K antagonist and is used for pediatric patients requiring long-term anticoagulation in the outpatient setting. Indications for long-term anticoagulation include the treatment of univentricular heart, VTE, the use of prosthetic valves in children and adolescents, and aneurysms following Kawasaki disease.5 The initial dose of warfarin is 0.2 mg/kg orally (maximum 5 mg).3 However, there are several limitations with the use of warfarin. One major limitation of warfarin is the narrow therapeutic index. A large pediatric retrospective study identified independent risk factors such as Asian race, drug interactions, mitral value replacement, and length of hospital stay that resulted in patients being readmitted to the hospital within 30 days due to warfarin-associated bleeding.6 Practitioners must also consider that many patients starting warfarin have comorbidities and require multiple medications that cause interactions; there may also be dietary interactions with infant formula that contains a large amount of vitamin K.2 Drug formulation is a concern as well, as many infants are unable to swallow tablets and warfarin is not commercially available as a liquid. Lastly, frequent visits to a healthcare provider for monitoring of warfarin are difficult and time consuming.
Unfractionated heparin (UFH): UFH is a commonly used IV anticoagulant for primary prophylaxis in the hospital setting, particularly for a patient in the intensive care unit or in preparation for a surgical procedure. Considerations in the pediatric population include the short half-life of UFH and limited data regarding efficacy of protamine to effectively reverse bleeding. The typical loading dose for patients is 75 mg/kg IV over 10 minutes.3 The maintenance dose is then separated based on age: Infants will receive 28 units/kg/hour; children aged 1 year and older and adolescents will receive 20 units/kg/hour.3 Limitations on use of UFH are due to the variability and interpretation of the two assays, activated partial thromboplastin time (aPTT) and heparin assay (anti-Xa). Another limitation is the need to extrapolate the adult therapeutic levels to children.4 A serious adverse reaction related to UFH therapy is heparin-induced thrombocytopenia (HIT). The incidence of HIT is reported to be 2.3% to 3.7%, with 1% to 3% prevalence in children undergoing cardiac surgery.7
LMWH: LMWH, administered subcutaneously, has a heparin-like structure, with higher selectivity for factor Xa than for thrombin when compared with heparin. Patients younger than age 2 months typically receive 1.5 mg/kg/dose, and patients older than age 2 months receive 1 mg/kg/dose for VTE treatment.3 One of the biggest benefits is that the longer half-life and stable pharmacokinetics of LMWH allow for outpatient use. LMWH has no food or drug interactions and requires less monitoring than warfarin. LMWH may require weekly monitoring of anti-Xa levels in children in the inpatient setting requiring therapeutic Xa levels. Although incident rates of HIT with LMWH therapy are unknown, the risk is thought to be lower than with UFH. Protamine is the reversal agent, but it can only partially reverse bleeding.2 LMWH also requires renal dose adjustments.
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.14,15 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.
Pharmacists working with pediatric patients must overcome barriers when selecting appropriate anticoagulation therapy. These include limited dosage formulations, lack of supporting literature for drug use, limited drug-therapy guidelines, and close monitoring during the major phases of growth and development, because pediatric dosing is typically weight-based dosing.
Anticoagulants are a class of drugs associated with a high risk for medication errors and adverse events, making monitoring of dosing and adherence to therapy essential. Institutions have begun implementing pharmacist-led protocols to monitor anticoagulation therapy for patients in adult and pediatric hospitals and outpatient clinics. Pharmacists working with interdisciplinary teams overseeing anticoagulant therapy in pediatric patients can look to the future to assist physicians in selecting therapies based on patient-specific factors, costs, safety and efficacy data, and oral dosage forms, especially with DOACs on the horizon.
The advantages of DOACs include oral dosage formulations, such as a suspension currently under study, minimal monitoring requirements, predictable pharmacokinetics, and no food interactions. Current guidelines for antithrombotic therapy in pediatric patients do not include recommendations for the use of DOACs. Current trials evaluating the safety and efficacy of DOAC therapy should, in the future, provide physicians and pharmacists with additional drug-therapy options and data to help guide and optimize anticoagulant therapy for pediatric patients.
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