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Semin Thromb Hemost 2021; 47(06): 643-653
DOI: 10.1055/s-0041-1725944
Review Article

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Pediatric Venous Thromboembolism Treatment and Thromboprophylaxis: A Systematic Review of the Literature

Joshua W. Branstetter   *
1   Department of Pharmacy, Children's Healthcare of Atlanta, Atlanta, Georgia
,
Amy L. Kiskaddon   *
2   Department of Pharmacy, The Johns Hopkins All Children's Hospital, St. Petersburg, Florida
3   Johns Hopkins All Children's Institute for Clinical and Translational Research, St. Petersburg, Florida
,
Madeleine A. King
4   Department of Pharmacy, C.S. Mott Children's Hospital, Ann Arbor, Michigan
,
Carli Coalter
5   College of Pharmacy, Union University, Jackson, Tennessee
,
Kimberly M. Grubbs
6   Department of Pharmacy, Medical University of South Carolina, Charleston, South Carolina
,
Hunter Fly
7   Department of Pharmacy, Le Bonheur Children's Hospital, Memphis, Tennessee
,
Christoph Male
8   Department of Paediatrics, Medical University of Vienna, Austria
,
Leonardo Brandão
9   Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
10   Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
,
Neil A. Goldenberg
3   Johns Hopkins All Children's Institute for Clinical and Translational Research, St. Petersburg, Florida
11   Thrombosis Program, Johns Hopkins All Children's Hospital, St. Petersburg, Florida
12   Department of Pediatrics and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Abstract

Venous thromboembolism (VTE) in children can lead to significant morbidity and mortality. Traditionally, treatment for thrombotic events in pediatric patients has been limited mainly to unfractionated heparin, low-molecular-weight heparin (LMWH), or vitamin K antagonists. Since the first non–vitamin K antagonist oral anticoagulant (NOAC) was approved for adult use, these agents have gained popularity for a variety of indications. This is largely due to their ease of administration, favorable pharmacokinetic and pharmacodynamic profile, decreased food interactions, and decreased need for therapeutic drug monitoring. Treating and preventing VTE with traditional anticoagulants in pediatric patients presents many challenges. This systematic review evaluated the current literature regarding pediatric NOAC trials. Additionally, based on an up-to-date query of clinicaltrials.gov, we detail current ongoing and as-yet unpublished clinical trials, study outcomes, and projected completion dates. Published pediatric NOAC trials have included 1,007 total children to date and have ranged from phase 1 to 4, with “indications” including both thromboembolism prophylaxis and VTE treatment. Three recent phase 3 trials, specifically involving rivaroxaban and dabigatran, have shown the agents to be at least as effective as traditional anticoagulants for acute and/or extended VTE treatment, with low frequency of recurrent thrombosis and clinically significant bleeding rates. Additionally, specially developed and tested pediatric formulations have allowed for accurate and reliable dosing, oral administration, stable pharmacokinetics and pharmacodynamics, and fewer drug or food interactions. Ongoing trials, anticipated for completion in the next few years, will reveal important information with regard to thromboembolism prophylaxis in special pediatric subpopulations and settings.

Keywords

pediatric VTE - thromboprophylaxis - NOACs

* These authors contributed equally, as co-first authors.




Publication History

Article published online:
10 May 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Goldenberg NA, Abshire T, Blatchford PJ. et al; Kids-DOTT Trial Investigators. Multicenter randomized controlled trial on Duration of Therapy for Thrombosis in Children and Young Adults (the Kids-DOTT trial): pilot/feasibility phase findings. J Thromb Haemost 2015; 13 (09) 1597-1605
    CrossrefPubMedSearch in Google Scholar
  • 2 van Ommen CH, Heijboer H, van den Dool EJ, Hutten BA, Peters M. Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome. J Thromb Haemost 2003; 1 (12) 2516-2522
    CrossrefPubMedSearch in Google Scholar
  • 3 Nowak-Göttl U, Junker R, Kreuz W. et al; Childhood Thrombophilia Study Group. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood 2001; 97 (04) 858-862
    CrossrefPubMedSearch in Google Scholar
  • 4 Goldenberg NA, Donadini MP, Kahn SR. et al. Post-thrombotic syndrome in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors. Haematologica 2010; 95 (11) 1952-1959
    CrossrefPubMedSearch in Google Scholar
  • 5 Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics 2009; 124 (04) 1001-1008
    CrossrefPubMedSearch in Google Scholar
  • 6 Monagle P, Chan AKC, 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 2014; 146 (06) 1694
    PubMedSearch in Google Scholar
  • 7 Mikler J, Samoš M, Bolek T. et al. Direct oral anticoagulants: novel approach for the treatment of thrombosis in pediatric patients?. Pediatr Cardiol 2019; 40 (07) 1431-1438
    CrossrefPubMedSearch in Google Scholar
  • 8 Raschi E, Bianchin M, Gatti M, Squizzato A, De Ponti F. Comparative effectiveness and safety of direct oral anticoagulants: overview of systematic reviews. Drug Saf 2019; 42 (12) 1409-1422
    CrossrefPubMedSearch in Google Scholar
  • 9 Eliquis [Apixaban]. Princeton, NJ: Bristol Myers Squibb Company; 2012
    Search in Google Scholar
  • 10 Male C, Thom K, O'Brien SH. Direct oral anticoagulants: What will be their role in children?. Thromb Res 2019; 173: 178-185
    CrossrefPubMedSearch in Google Scholar
  • 11 Goldenberg NA, Takemoto CM, Yee DL, Kittelson JM, Massicotte MP. Improving evidence on anticoagulant therapies for venous thromboembolism in children: key challenges and opportunities. Blood 2015; 126 (24) 2541-2547
    CrossrefPubMedSearch in Google Scholar
  • 12 Newall F, Branchford B, Male C. Anticoagulant prophylaxis and therapy in children: current challenges and emerging issues. J Thromb Haemost 2018; 16 (02) 196-208
    CrossrefPubMedSearch in Google Scholar
  • 13 Pradaxa (Dabigatran). Ingelheim, Germany. Boehringer Ingelheim Pharmaceuticals Inc.; 2010
    PubMedSearch in Google Scholar
  • 14 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 (04) 630-635
    CrossrefPubMedSearch in Google Scholar
  • 15 Halton JM, Lehr T, Cronin L. et al. Safety, tolerability and clinical pharmacology of dabigatran etexilate in adolescents. An open-label phase IIa study. Thromb Haemost 2016; 116 (03) 461-471
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Halton JML, Albisetti M, Biss B. et al. Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability. J Thromb Haemost 2017; 15 (11) 2147-2157
    CrossrefPubMedSearch in Google Scholar
  • 17 Halton JML, Picard AC, Harper R. et al. Pharmacokinetics, pharmacodynamics, safety and tolerability of dabigatran etexilate oral liquid formulation in infants with venous thromboembolism. Thromb Haemost 2017; 117 (11) 2168-2175
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 NCT02044367, Boehringer Ingelheim. Relative Bioavailability of Dabigatran Capsules, Pellets and Oral Solution in Healthy Volunteers. . In: ClinicalTrials.gov. Bethesda, MD: National Library of Medicine; 2000
    PubMed
  • 19 Maas H, Gropper S, Huang F. et al. Anticoagulant effects of dabigatran in paediatric patients compared with adults: combined data from three paediatric clinical trials. Thromb Haemost 2018; 118 (09) 1625-1636
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Halton J, Brandão LR, Luciani M. et al; DIVERSITY Trial Investigators. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial. Lancet Haematol 2021; 8 (01) e22-e33
    CrossrefPubMedSearch in Google Scholar
  • 21 Brandão LR, Albisetti M, Halton J. et al; DIVERSITY Study Investigators. Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children. Blood 2020; 135 (07) 491-504
    CrossrefPubMedSearch in Google Scholar
  • 22 Xarelto (Rivaroxaban). Titusville, NJ: Janssen Pharmaceuticals Inc; 2020
    PubMed
  • 23 Willmann S, Becker C, Burghaus R. et al. Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban. Clin Pharmacokinet 2014; 53 (01) 89-102
    CrossrefPubMedSearch in Google Scholar
  • 24 Attard C, Monagle P, Kubitza D, Ignjatovic V. The in vitro anticoagulant effect of rivaroxaban in children. Thromb Res 2012; 130 (05) 804-807
    CrossrefPubMedSearch in Google Scholar
  • 25 Kubitza D, Willmann S, Becka M. et al. Exploratory evaluation of pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study. Thromb J 2018; 16 (01) 31
    CrossrefPubMedSearch in Google Scholar
  • 26 Willmann S, Thelen K, Kubitza D. et al. Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study. Thromb J 2018; 16 (01) 32
    CrossrefPubMedSearch in Google Scholar
  • 27 Monagle P, Lensing AWA, Thelen K. et al; EINSTEIN-Jr Phase 2 Investigators. Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies. Lancet Haematol 2019; 6 (10) e500-e509
    CrossrefPubMedSearch in Google Scholar
  • 28 Male C, Lensing AWA, Palumbo JS. et al; EINSTEIN-Jr Phase 3 Investigators. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematol 2020; 7 (01) e18-e27
    CrossrefPubMedSearch in Google Scholar
  • 29 Young G, Lensing AWA, Monagle P. et al; EINSTEIN-Jr. Phase 3 Investigators. Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation. J Thromb Haemost 2020; 18 (07) 1672-1685
    CrossrefPubMedSearch in Google Scholar
  • 30 NCT02846532, Janssen Research & Development, LLC., Pharmacokinetic, Pharmacodynamic, Safety, and Efficacy Study of Rivaroxaban for Thromboprophylaxis in Pediatric Participants 2 to 8 Years of Age after the Fontan Procedure (UNIVERSE). In: ClinicalTrials.gov. Raritan, NJ. National Library of Medicine; 2000
    PubMed
  • 31 Key NS, Khorana AA, Kuderer NM. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2020; 38 (05) 496-520
    CrossrefPubMedSearch in Google Scholar
  • 32 Bauer KA. How effective and safe is factor XI inhibition in preventing venous thrombosis?. JAMA 2020; 323 (02) 121-122
    CrossrefPubMedSearch in Google Scholar
  • 33 Granger CB, Alexander JH, McMurray JJ. et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
    CrossrefPubMedSearch in Google Scholar
  • 34 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST-guideline and expert panel report. Chest 2016; 149 (02) 315-352
    CrossrefPubMedSearch in Google Scholar
  • 35 Agnelli G, Buller HR, Cohen A. et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (08) 699-708
    CrossrefPubMedSearch in Google Scholar
  • 36 Raskob GE, Gallus AS, Pineo GF. et al. Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials. J Bone Joint Surg Br 2012; 94 (02) 257-264
    CrossrefPubMedSearch in Google Scholar
  • 37 NCT01707394, Bristol Myers Squibb, Study to Evaluate a Single Dose of Apixaban in Pediatric Participants at Risk for a Thrombotic Disorder. In: ClinicalTrials.gov. Bethesda, MD: National Library of Medicine; 2000
    PubMed
  • 38 O'Brien SH, Li D, Mitchell LG. et al. PREVAPIX-ALL: apixaban compared to standard of care for prevention of venous thrombosis in paediatric acute lymphoblastic leukaemia (ALL)-rationale and design. Thromb Haemost 2019; 119 (05) 844-853
    Thieme ConnectPubMedSearch in Google Scholar
  • 39 NCT02369653, Bristol Myers Squibb, A study of the safety and effectiveness of apixaban in preventing blood clots in children with leukemia who have a central venous catheter and are treated with asparaginase. In: ClinicalTrials.gov. Bethesda, MD: National Library of Medicine; 2000
    PubMed
  • 40 Payne RM, Burns KM, Glatz AC. et al; Pediatric Heart Network Investigators. A multi-national trial of a direct oral anticoagulant in children with cardiac disease: design and rationale of the Safety of ApiXaban On Pediatric Heart disease On the preventioN of Embolism (SAXOPHONE) study. Am Heart J 2019; 217: 52-63
    CrossrefPubMedSearch in Google Scholar
  • 41 NCT02981472, Bristol Myers Squibb, A study of the safety and pharmacokinetics of apixaban versus vitamin K antagonist (VKA) or low molecular weight heparin (LMWH) in pediatric subjects with congenital or acquired heart disease requiring anticoagulation. In: ClincalTrials.gov. Bethesda, MD: National Library of Medicine; 2000
    PubMed
  • 42 NCT02464969, Pfizer. Apixaban for the acute treatment of venous thromboembolism in children. In: ClincalTrials.gov. Bethesda, MD: National Library of Medicine; 2000
    PubMedSearch in Google Scholar
  • 43 NCT04041843, New York Medical College. A pilot study of an oral anticoagulant apixaban for the treatment of venous thromboembolism in children and adolescents. In: ClinicalTrials.gov. Bethesda, MD: National Library of Medicine; 2000
    PubMedSearch in Google Scholar
  • 44 Annex to the European Commission guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’. European Medicines Agency. 2017
    PubMedSearch in Google Scholar
  • 45 Lixiana (Edoxaban) [package insert]. Tokyo, Japan. Daiichi Sankyo Inc.; 2015
    PubMed
  • 46 NCT02303431, Daiichi Sankyo, Inc. Phase 1 Pediatric Pharmacokinetics/Pharmacodynamics (PK/PD) Study. In: ClincalTrials.gov. National Library of Medicine; 2000
    PubMed
  • 47 NCT03395639, Daiichi Sankyo, Inc. Edoxaban for Prevention of Blood Vessels Being Blocked by Clots (Thrombotic Events) in Children at Risk Because of Cardiac Disease. . In: ClincalTrials.gov. National Library of Medicine; 2000
    PubMed
  • 48 NCT02798471, Daiichi Sankyo, Inc. Hokusai Study in Pediatric Patients with Confirmed Venous Thromboembolism (VTE). . In: ClincalTrials.gov. National Library of Medicine; 2000
    PubMed
  • 49 van Ommen CH, Albisetti M, Chan AK. et al. The Edoxaban Hokusai VTE PEDIATRICS Study: an open-label, multicenter, randomized study of edoxaban for pediatric venous thromboembolic disease. Res Pract Thromb Haemost 2020; 4 (05) 886-892
    CrossrefPubMedSearch in Google Scholar