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Direct Oral Anticoagulants – Are They Ready for Primetime in the Pediatric Population?
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A 13-year-old girl (110 kg) with a history of asthma, depression, and attention deficit disorder presents to the emergency department with a swollen right leg which was warm and painful to the touch. The pain is unrelieved by acetaminophen and ibuprofen that she took prior to getting medical attention. She was recently on a trip to Australia and came back a few days ago. Her home medications include oral contraceptive, albuterol inhaler as needed, fluoxetine, and lisdexamfetamine. Physical exam was notable for a tender right calf with mild edema of the ankle. The exam was otherwise unremarkable. The only significant laboratory finding is an elevated D-dimer of 3 mcg/mL. A bilateral venous duplex is obtained and shows that the right lower extremity is positive for deep and superficial vein thrombosis involving the right popliteal and posterior tibial veins. Subcutaneous enoxaparin 1 mg/kg/dose every 12 hours is started for the deep vein thrombosis and the medical team is trying to decide on a long-term oral anticoagulant for this patient.
Based on the current literature, which one of the following oral anticoagulants is most appropriate upon discharge of this patient?
Show Answer
The correct answer is: E. Warfarin daily adjusted for an INR goal of 2-3 with at least 5 days of enoxaparin overlap.
Venous thromboembolism (VTE) can occur in pediatric patients as in adults. Historically, unfractionated heparin (UFH), low molecular weight heparin (LMWH), or warfarin is often the anticoagulant of choice in this former population.1 Newer oral anticoagulants, better known as direct oral anticoagulants (i.e. apixaban, dabigatran, edoxaban, and rivaroxaban), are now available and approved for use in adults. Many practitioners have gained interest in potentially using one of these agents in pediatric patients, and thus few studies have been published and many more are underway evaluating their efficacy in this special population.
Apixaban is a reversible factor Xa inhibitor. Published data evaluating its efficacy in pediatric patients do not currently exist. In 2012, a pharmacokinetic study was performed in patients aged 12 to <18 years who received either 0.66 mg/m2 or 1.32 mg/m2 apixaban twice-daily, but it was terminated for unknown reasons.2 There are currently three ongoing studies (one phase I, one phase III, and one phase IV).3-6 The phase IV study includes neonates to subjects <18-years-old with confirmed VTE. The subjects will be randomized to receive either apixaban or standard of care (i.e. UFH, LMWH, and/or warfarin). The dose of apixaban is dependent on the subjects' age and weight: 1) <12 years: dose not yet determined; 2) 12 to <18 years and ≤40 kg: 0.2 mg/kg twice-daily for 7 days, then 0.1 mg/kg/day twice-daily; and 3) 12 to <18 years and >40 kg: 10 mg twice-daily for 7 days, then 5 mg twice-daily. The primary endpoints will be the composite number of bleeding and symptomatic or asymptomatic recurrent VTE or mortality for up to three months.6
Dabigatran is a direct thrombin inhibitor that has the most published data and ongoing trials by far, aside from rivaroxaban. One completed study showed that there was not any difference in the response to increasing dabigatran concentrations at different age groups, but longer clotting times were observed in children than in adults.7 A phase II study evaluated the safety and tolerability of dabigatran in nine subjects with a mean age of 15.7 ± 1.3 years.8 The study medication was adjusted to a target dose of 2.14 mg/kg, with a max of 150 mg dabigatran twice-daily. The total dabigatran concentrations were 34.2 ng/mL and 58.2 ng/mL in subjects who had 100 mg twice-daily and 125 mg twice-daily, respectively.8 Currently, there are two phase II studies evaluating a liquid formulation of dabigatran9-10 (Note: one similar phase II study was recently withdrawn for unknown reason11), and two phase III studies evaluating the safety and efficacy of this medication in the pediatric population.12-13 One of these phase III studies aims to include 270 patients <18-years-old with confirmed VTE who have been treated with UFH or LMWH for five to seven days.12 The subjects will be randomized to either an age- and weight-appropriate dose of dabigatran (exact dose not mentioned) twice-daily, or standard of care (LMWH or warfarin) for three months. The primary endpoints include combined efficacy of complete thrombus resolution and freedom from recurrent VTE, mortality, and major bleeding events for up to three months.12
Edoxaban is the most recently-available factor Xa inhibitor in the United States. To date, there are no completed or published studies on edoxaban in pediatric patients; however, there is one phase I pharmacokinetic/pharmacodynamic study being performed in patients <18-years-old who will be divided into eight arms according to their age and dose of edoxaban (i.e. low or high matched adult doses [30 and 60 mg, respectively]).14
Rivaroxaban is another factor Xa inhibitor that has more published data and ongoing trials in pediatric patients similar to dabigatran. There are currently four completed studies that assessed the pharmacokinetic and pharmacodynamic effects of rivaroxaban in pediatric patients.15-18 One of these studies developed a pharmacokinetic model for rivaroxaban 10 mg and 20 mg in adults scaled to pediatric patients <18-years-old (0.143 mg/kg and 0.286 mg/kg, respectively). Overall, the area under the curve (AUC) and 24-h concentration (C24h) values were similar in most weight groups except for <40 kg and >70 kg. In simulated subjects <40 kg, the AUC and C24h were much lower than the adult reference population, so higher weight-based doses may be necessary. On the other hand, these values were much higher in subjects more than 70 kg than in the adult reference, so the weight-based doses may be higher than the 10 mg or 20 mg adult doses.15 Currently, there are one phase I, one phase I/II, two phase II, and one phase III studies being performed on rivaroxaban in pediatric patients.19-23 The phase III study will include patients six months to <18-years-old with confirmed VTE who have received UFH, LMWH, or fondaparinux for at least three months prior to enrollment.23 The patients will be randomized to standard of care (LMWH, warfarin, or fondaparinux) or rivaroxaban. Patients six months to <12-years-old will receive rivaroxaban 20 mg equivalent suspension twice-daily; and 12 to 18 years old, 20 mg equivalent tablet once-daily. The primary endpoints include the composite number of all symptomatic recurrent VTE and major or non-major bleeding for up to three months.23
Due to the limited published pediatric literature available on the direct oral anticoagulants and the lack of information on dosing reversal agents in children, it is still too early to recommend using them for VTE in this population. For now, warfarin should still be the oral anticoagulant of choice for pediatric patients.
References
- Monagle P, Chan AK, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e737S-801S.
- Bristol-Myers Squibb. Multiple-dose study apixaban in pediatric subjects with an indwelling central venous catheter. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT01195727. https://clinicaltrials.gov/ct2/show/NCT01195727. Accessed 28 Jan 2016.
- Bristol-Myers Squibb. Study to evaluate a single dose of apixaban in pediatric subjects at risk for a thrombotic disorder. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM Identifier: NCT01707394. https://clinicaltrials.gov/ct2/show/NCT01707394. Accessed 28 Jan 2016.
- Rodriguez V, O'Brien S, Sung L, et al. Rationale and design of AESOP: apixaban for prevention of deep vein thrombosis in pediatric patients with acute lymphoblastic leukemia or lymphoma treated with L-asparaginase. J Throm Haemost 2015;13:425.
- Bristol-Myers Squibb. Safety and efficacy study of apixaban to prevent clots in children with leukemia who have a central venous catheter and are treated with Peg Asparaginase. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM Identifier: NCT02369653. https://clinicaltrials.gov/ct2/show/NCT02369653. Accessed 28 Jan 2016.
- Pfizer. Apixaban for the acute treatment of venous thromboembolism in children. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM Identifier: NCT02464969. https://clinicaltrials.gov/ct2/show/NCT02464969. Accessed 28 Jan 2016.
- Dietrich K, Stang L, Van Ryn J, Mitchell LG. Assessing the anticoagulant effect of dabigatran in children: an in vitro study. Thromb Res 2015;135:630–5.
- Boehringer Ingelheim. Safety and tolerability of dabigatran etexilate in adolescents. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM Identifier: NCT00844415. https://clinicaltrials.gov/ct2/show/NCT00844415. Accessed 28 Jan 2016.
- Boehringer Ingelheim. Tolerability, PK/PD and safety of dabigatran etexilate oral liquid formulation in children < 1 year of age. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT02223260. https://clinicaltrials.gov/ct2/show/NCT02223260. Accessed 28 Jan 2016.
- Boehringer Ingelheim. Safety and tolerability of dabigatran etexilate solution in children 1 to < 12 years of age. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT01083732. https://clinicaltrials.gov/ct2/show/NCT01083732. Accessed 28 Jan 2016.
- Boehringer Ingelheim. Pharmacokinetics, safety and tolerability of dabigatran etexilate solution in children 1 to <2 years of age. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT01773174. https://clinicaltrials.gov/ct2/show/NCT01773174. Accessed 28 Jan 2016.
- Boehringer Ingelheim. Open label study comparing efficacy and safety of dabigatran etexilate to standard of care in paediatric patients with venous thromboembolism (VTE). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT01895777. https://clinicaltrials.gov/ct2/show/record/NCT01895777. Accessed 28 Jan 2016.
- Boehringer Ingelheim. Safety of dabigatran etexilate in blood clot prevention in children. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT02197416. https://clinicaltrials.gov/ct2/show/NCT02197416. Accessed 28 Jan 2016.
- Daiichi Sanyko. A Phase 1, open-label, single-dose, non-randomized study to evaluate pharmacokinetics and pharmacodynamics of edoxaban in pediatric patients. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT02303431. https://clinicaltrials.gov/ct2/show/NCT02303431. Accessed 28 Jan 2016.
- Willmann S, Becker C, Burghaus R, et al. Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban. Clin Pharmacokinet 2014;53:89–102.
- Attard C, Monagle P, Kubitza D, et al. The in vitro anticoagulant effect of rivaroxaban in children. Thromb Res. 2012;130:804–7.
- Young G, Kubitza D, Chan A, et al. Development of a rivaroxaban dosing regimen for treatment of VTE in children aged 12 to 18 years. J Throm Haemost 2015;13:37.
- Bayer. Rivaroxaban pharmacokinetics/ pharmacodynamics (PK/PD) study in pediatric subjects. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM Identifier: NCT01145859. https://clinicaltrials.gov/ct2/show/NCT01145859. Accessed 28 Jan 2016.
- Bayer. Phase I study on rivaroxaban dry powder suspension in children. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM Identifier: NCT02497716. https://clinicaltrials.gov/ct2/show/NCT02497716. Accessed 28 Jan 2016.
- Bayer. Rivaroxaban for treatment in venous or arterial catheter related thrombosis in neonates. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM Identifier: NCT02564718. https://clinicaltrials.gov/ct2/show/NCT02564718. Accessed 28 Jan 2016.
- Bayer. EINSTEIN Junior Phase II: Oral rivaroxaban in young children with venous thrombosis (EINSTEINJr). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM Identifier: NCT02309411. https://clinicaltrials.gov/ct2/show/NCT02309411. Accessed 28 Jan 2016.
- Bayer. Oral rivaroxaban in children with venous thrombosis (EINSTEINJunior). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM Identifier: 01684423. https://clinicaltrials.gov/ct2/show/NCT01684423. Accessed 28 Jan 2016.
- Bayer. EINSTEIN Junior Phase III: oral rivaroxaban in children with venous thrombosis (EINSTEIN Jr). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM Identifier: NCT02234843. https://clinicaltrials.gov/ct2/show/NCT02234843. Accessed 28 Jan 2016.
