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Thromb Haemost 2019; 119(12): 2034-2042
DOI: 10.1055/s-0039-1697027
Stroke, Systemic or Venous Thromboembolism
Georg Thieme Verlag KG Stuttgart · New York

Effectiveness and Safety of Primary Thromboprophylaxis in Children with Cancer: A Systematic Review of the Literature and Network Meta-Analysis

Marie-Claude Pelland-Marcotte 
1   Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada
2   Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Canada
,
Soumitra Tole
1   Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada
,
Petros Pechlivanoglou
2   Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Canada
3   Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Canada
,
Leonardo Rodrigues Brandão
1   Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada
2   Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Canada
› Author Affiliations Funding M.C.P.M. received support from the Canadian Institutes of Health Research Doctoral Research Award.
Further Information

Publication History

09 May 2019

23 July 2019

Publication Date:
10 October 2019 (online)

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Abstract

Thromboembolism (TE) is a well-recognized complication of pediatric cancer and can lead to mortality and excess morbidity. There is conflicting evidence about the effectiveness and safety of thromboprophylaxis in children. We conducted a systematic literature review and network meta-analysis of primary pharmacological thromboprophylaxis in children and adolescents (0–21 years) with cancer. The primary outcomes were objectively proven TE and major bleeding. The network meta-analysis included comparisons of multiple alternatives simultaneously: antithrombin (AT) replacement, low molecular weight heparin (LMWH), vitamin K antagonists (VKAs), and standard of care (SOC) defined as no thromboprophylaxis or low-dose heparin for catheter patency. Six articles describing 1,318 patients were included (mean age: 6.7 years, 56.7% male). Acute lymphoblastic leukemia was the underlying diagnosis in 97.5% of patients. All studies were considered at moderate or high risk of bias. LMWH was the only agent associated with lower odds of TE compared with SOC (odds ratio [OR]: 0.23, 95% confidence interval [CI]: 0.06–0.81). No statistically significant difference was detected between other thromboprophylaxis modalities and SOC. Tau2 and I 2 suggested a high degree of heterogeneity. No statistically significant differences in the odds of major bleeding were found between AT replacement, LMWH, VKA, and SOC. Current evidence suggests that low-dose LMWH is effective and safe to prevent TE in children with cancer but is insufficient to conclude if AT replacement or VKA are effective thromboprophylaxis options. Further research, notably randomized controlled trials enrolling children with diverse types of cancer, is crucially needed.

Keywords

thrombosis - cancer - thromboprophylaxis - children

Supplementary Material

 

  • References

  • 1 Athale U. Thrombosis in pediatric cancer: identifying the risk factors to improve care. Expert Rev Hematol 2013; 6 (05) 599-609
    CrossrefPubMedGoogle Scholar
  • 2 Asyyed Z, MacDonald T, Digout C, Kulkarni K. Incidence and characteristics of venous thrombotic events in pediatric cancer patients: a 20-year experience in the Maritimes, Canada. Pediatr Hematol Oncol 2017; 34 (02) 90-99
    CrossrefPubMedGoogle Scholar
  • 3 Athale U, Cox S, Siciliano S, Chan AK. Thromboembolism in children with sarcoma. Pediatr Blood Cancer 2007; 49 (02) 171-176
    CrossrefPubMedGoogle Scholar
  • 4 Pelland-Marcotte MC, Pole JD, Kulkarni K. , et al. Thromboembolism incidence and risk factors in children with cancer: a population-based cohort study. Thromb Haemost 2018; 118 (09) 1646-1655
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 O'Brien SH, Klima J, Termuhlen AM, Kelleher KJ. Venous thromboembolism and adolescent and young adult oncology inpatients in US children's hospitals, 2001 to 2008. J Pediatr 2011; 159 (01) 133-137
    CrossrefPubMedGoogle Scholar
  • 6 Piovesan D, Attard C, Monagle P, Ignjatovic V. Epidemiology of venous thrombosis in children with cancer. Thromb Haemost 2014; 111 (06) 1015-1021
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Caruso V, Iacoviello L, Di Castelnuovo A. , et al. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood 2006; 108 (07) 2216-2222
    PubMedGoogle Scholar
  • 8 Forbrigger Z, Digout C, Fernandez C, Bernstein M, Kulkarni K. Significantly inferior overall and event free survival in pediatric oncology patients with symptomatic venous thrombotic events as compared to those without symptomatic venous thrombotic events: a population based study from Maritimes, Canada. Am Soc Hematol 2016; 128 (22) 393
    PubMedGoogle Scholar
  • 9 Kulkarni K, Halton J, Spavor M. , et al. Increased requirement for central venous catheter replacement in paediatric oncology patients with deep venous thrombosis: a multicentre study. Thromb Haemost 2015; 113 (02) 434-435
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Polen E, Weintraub M, Stoffer C, Jaffe DH, Burger A, Revel-Vilk S. Post-thrombotic syndrome after central venous catheter removal in childhood cancer survivors: a prospective cohort study. Pediatr Blood Cancer 2015; 62 (02) 285-290
    CrossrefPubMedGoogle Scholar
  • 11 Sébire G, Tabarki B, Saunders DE. , et al. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. Brain 2005; 128 (Pt 3): 477-489
    CrossrefPubMedGoogle Scholar
  • 12 Di Nisio M, Porreca E, Candeloro M, De Tursi M, Russi I, Rutjes AW. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev 2016; 12: CD008500
    PubMedGoogle Scholar
  • 13 Biss T, Monagle P. Antithrombotic therapy in children. In: Blanchette VS, Brandão LR, Breakey VR, Revel-Vilk S, eds. SickKids Handbook of Pediatric Thrombosis and Hemostasis. Basel, Switzerland: Karger Publishers; 2013: 214-231
    CrossrefGoogle Scholar
  • 14 Akl EA, Ramly EP, Kahale LA. , et al. Anticoagulation for people with cancer and central venous catheters. Cochrane Database Syst Rev 2014; (10) CD006468
    PubMedGoogle Scholar
  • 15 Meister B, Kropshofer G, Klein-Franke A, Strasak AM, Hager J, Streif W. Comparison of low-molecular-weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2008; 50 (02) 298-303
    CrossrefPubMedGoogle Scholar
  • 16 Mitchell L, Andrew M, Hanna K. , et al. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thromb Haemost 2003; 90 (02) 235-244
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Schwarzer G, Carpenter JR, Rücker G. Meta-analysis with R. Switzerland: Springer; 2015
    Google Scholar
  • 18 Mitchell LG, Goldenberg NA, Male C, Kenet G, Monagle P, Nowak-Göttl U. ; Perinatal and Paediatric Haemostasis Subcommittee of the SSC of the ISTH. Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children. J Thromb Haemost 2011; 9 (09) 1856-1858
    CrossrefPubMedGoogle Scholar
  • 19 Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33 (01) 159-174
    CrossrefPubMedGoogle Scholar
  • 20 Stem J, Christensen A, Davis D, Raffini L. Safety of prophylactic anticoagulation at a pediatric hospital. J Pediatr Hematol Oncol 2013; 35 (07) e287-e291
    CrossrefPubMedGoogle Scholar
  • 21 Massicotte P, Julian JA, Gent M. , et al; PROTEKT Study Group. An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial. Thromb Res 2003; 109 (2-3): 101-108
    CrossrefPubMedGoogle Scholar
  • 22 Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998; 52 (06) 377-384
    CrossrefPubMedGoogle Scholar
  • 23 Higgins JP, Altman DG. Assessing risk of bias in included studies. Cochrane handbook for systematic reviews of interventions; 2008: 187-241 . Available at: http://handbook.cochrane.org . Accessed September 7, 2019
    PubMedGoogle Scholar
  • 24 Gart JJ, Nam J. Approximate interval estimation of the ratio of binomial parameters: a review and corrections for skewness. Biometrics 1988; 44 (02) 323-338
    CrossrefPubMedGoogle Scholar
  • 25 Mills EJ, Thorlund K, Ioannidis JP. Demystifying trial networks and network meta-analysis. BMJ 2013; 346: f2914
    CrossrefPubMedGoogle Scholar
  • 26 Hoaglin DC, Hawkins N, Jansen JP. , et al. Conducting indirect-treatment-comparison and network-meta-analysis studies: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 2. Value Health 2011; 14 (04) 429-437
    CrossrefPubMedGoogle Scholar
  • 27 Borenstein M, Hedges LV, Higgins JP, Rothstein HR. Identifying and Quantifying Heterogeneity. In: Introduction to Meta-Analysis. Chichester, United Kingdom: John Wiley & Sons, Ltd; 2009: 107-126
    CrossrefGoogle Scholar
  • 28 Hutton B, Salanti G, Caldwell DM. , et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med 2015; 162 (11) 777-784
    CrossrefPubMedGoogle Scholar
  • 29 Mitchell L, Lambers M, Flege S. , et al. Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study. Blood 2010; 115 (24) 4999-5004
    CrossrefPubMedGoogle Scholar
  • 30 Ruud E, Holmstrøm H, De Lange C, Hogstad EM, Wesenberg F. Low-dose warfarin for the prevention of central line-associated thromboses in children with malignancies--a randomized, controlled study. Acta Paediatr 2006; 95 (09) 1053-1059
    CrossrefPubMedGoogle Scholar
  • 31 Elhasid R, Lanir N, Sharon R. , et al. Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinolysis 2001; 12 (05) 367-370
    CrossrefPubMedGoogle Scholar
  • 32 Greiner J, Schrappe M, Claviez A. , et al. THROMBOTECT-a randomized study comparing low molecular weight heparin, antithrombin and unfractionated heparin for thromboprophylaxis during induction therapy of acute lymphoblastic leukemia in children and adolescents. Haematologica 2019; 104 (04) 756-765
    CrossrefPubMedGoogle Scholar
  • 33 Mitchell LG, Andrew M, Hanna K. , et al; Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase Group (PARKAA). A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with L-asparaginase: results of the Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) Study. Cancer 2003; 97 (02) 508-516
    CrossrefPubMedGoogle Scholar
  • 34 Carrier M, Abou-Nassar K, Mallick R. , et al; AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med 2019; 380 (08) 711-719
    CrossrefPubMedGoogle Scholar
  • 35 Rossel A, Robert-Ebadi H, Combescure C. , et al. Anticoagulant therapy for acute venous thrombo-embolism in cancer patients: a systematic review and network meta-analysis. PLoS One 2019; 14 (03) e0213940
    CrossrefPubMedGoogle Scholar
  • 36 Parmar N, Berry LR, Post M, Chan AK. Effect of covalent antithrombin-heparin complex on developmental mechanisms in the lung. Am J Physiol Lung Cell Mol Physiol 2009; 296 (03) L394-L403
    CrossrefPubMedGoogle Scholar
  • 37 Corral J, Rivera J, Guerrero JA. , et al. Latent and polymeric antithrombin: clearance and potential thrombotic risk. Exp Biol Med (Maywood) 2007; 232 (02) 219-226
    PubMedGoogle Scholar
  • 38 Schoot RA, van de Wetering MD, Stijnen T. , et al; DCOG-Aristocaths Supportive Care Working Group. Prevalence of symptomatic and asymptomatic thrombosis in pediatric oncology patients with tunneled central venous catheters. Pediatr Blood Cancer 2016; 63 (08) 1438-1444
    CrossrefPubMedGoogle Scholar
  • 39 Journeycake JM, Buchanan GR. Catheter-related deep venous thrombosis and other catheter complications in children with cancer. J Clin Oncol 2006; 24 (28) 4575-4580
    CrossrefPubMedGoogle Scholar
  • 40 Klaassen ILM, Lauw MN, van de Wetering MD. , et al. Tropic ALL study: thromboprophylaxis in children treated for acute lymphoblastic leukemia with low-molecular-weight heparin: a multicenter randomized controlled trial. BMC Pediatr 2017; 17 (01) 122
    CrossrefPubMedGoogle Scholar
  • 41 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
    Article in Thieme ConnectPubMedGoogle Scholar