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Systemic treatments for the prevention of venous thrombo-embolic events in paediatric cancer patients with tunnelled central venous catheters

  1. Reineke A Schoot1,*,
  2. Leontien CM Kremer1,
  3. Marianne D van de Wetering1,
  4. Cornelia H van Ommen2

Editorial Group: Cochrane Childhood Cancer Group

Published Online: 11 SEP 2013

DOI: 10.1002/14651858.CD009160.pub2


How to Cite

Schoot RA, Kremer LCM, van de Wetering MD, van Ommen CH. Systemic treatments for the prevention of venous thrombo-embolic events in paediatric cancer patients with tunnelled central venous catheters. Cochrane Database of Systematic Reviews 2013, Issue 9. Art. No.: CD009160. DOI: 10.1002/14651858.CD009160.pub2.

Author Information

  1. 1

    Emma Children's Hospital / Academic Medical Center, Department of Paediatric Oncology, Amsterdam, Netherlands

  2. 2

    Emma Children's Hospital / Academic Medical Center, Department of Paediatric Haematology, Amsterdam, Netherlands

*Reineke A Schoot, Department of Paediatric Oncology, Emma Children's Hospital / Academic Medical Center, PO Box 22660, Amsterdam, 1100 DD, Netherlands. r.a.schoot@amc.uva.nl.

Publication History

  1. Publication Status: New
  2. Published Online: 11 SEP 2013

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Characteristics of included studies [author-defined order]

MethodsRetrospective CCT conducted in two centres: the IWK in Halifax, Nova Scotia (Canada), and the BCCH in Vancouver, British Columbia (Canada)


Participants719 paediatric patients with ALL, treated between 1990 and 2005. Type of CVC was not mentioned. Mean age of patients treated at the IWK was 6.1 years (range 0.2 to 17.6), and mean age of patients treated at the BCCH was 6.1 years (range 0 to 17.2)


InterventionsFFP and/or cryoprecipitate supplementation (n = 240, experimental group) versus no supplementation (n = 479, control group)

Criteria for prophylaxis at the IWK changed over time: < 2001 FFP was supplemented when AT was < 50% of the lower limit of normal range, > 2001 FFP was supplemented when AT was < 50 U/mL. For the purpose of the study, any replacement provided at an AT level of 40 to 60 U/mL was deemed to be in accordance with these criteria

Cryoprecipitate was supplemented: < 2001 if fibrogen levels were < 50% of the lower limit of normal, > 2001 if fibrogen levels were < 1 g/L. For the purpose of the study, cryoprecipitate replacement at fibrinogen levels of 0.8 to 1.2 g/L was deemed to be in keeping with these criteria

86/240 participants received FFP supplementation and 163/240 cryoprecipitate


Outcomes
  • Symptomatic VTE: central nervous system thrombosis, defined as one that presented with central nervous system-related symptoms and was documented by computed tomography or magnetic resonance imaging
  • Adverse events: major bleeding: central nervous system haemorrhage, defined as one that presented with central nervous system-related symptoms and was documented by computed tomography or magnetic resonance imaging


NotesFollow-up data (median 11.7 years) were available for 7 participants with CNS thrombosis


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskCCT, no randomisation was performed

Allocation concealment (selection bias)High riskCCT, no randomisation was performed

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete reporting for all outcome measures investigated

Selective reporting (reporting bias)Low riskComplete reporting for all outcome measures investigated

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants and personnel

Blinding of outcome assessment symptomatic VTE (detection bias)High riskNo blinding of outcome assessors

Blinding of outcome assessment major bleeding, minor bleeding, thrombocytopenia, HIT, HITT, death due to (a)symptomatic VTE, removal of CVC because of (a)symptomatic VTE, CVC-related infection and CVC-related bacteraemia and/or post-thrombotic syndrome (detection bias)High riskMajor bleeding was evaluated; no blinding of outcome assessors


MethodsSingle-centre CCT performed in Haifa, Israel


Participants91 paediatric patients with ALL (> 12 months) treated between January 1989 and July 1999. Types of CVCs not mentioned


InterventionsEnoxaparin prophylaxis (n = 41, experimental group; treated between June 1994 and July 1999) versus no intervention (n = 50, control group; treated between January 1989 and January 1994)

Enoxaparin, an LMWH, was administered subcutaneously every 24 hours, median dose 0.84 mg/kg/d (range 0.45 to 1.33 mg/kg/d), starting with the first dose of asparaginase until one week after the last dose of asparaginase


Outcomes
  • Symptomatic VTE, any location, defined as clinical symptoms and signs of VTE verified radiologically
  • Adverse events: any bleeding episode, no definitions provided


NotesFollow-up data available only during asparaginase therapy


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskCCT; no randomisation performed

Allocation concealment (selection bias)High riskCCT; no randomisation performed

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete reporting on both groups

Selective reporting (reporting bias)Low riskComplete reporting for all outcome measures investigated

Blinding of participants and personnel (performance bias)
All outcomes
High riskCCT with historical control group, no blinding performed

Blinding of outcome assessment symptomatic VTE (detection bias)High riskNo blinding of outcome assessors

Blinding of outcome assessment major bleeding, minor bleeding, thrombocytopenia, HIT, HITT, death due to (a)symptomatic VTE, removal of CVC because of (a)symptomatic VTE, CVC-related infection and CVC-related bacteraemia and/or post-thrombotic syndrome (detection bias)High riskBleeding was evaluated (no specification for minor or major bleeding was provided); no blinding of outcome assessors


MethodsMulti-national, multi-centre open-label RCT conducted in Canada, Australia, United Kingdom, Germany and the USA


Participants186 paediatric patients with CVCs treated between Aprill 22, 1998 and December 31, 1999

Mean age of participants treated in the experimental group was 6.1 years (range 0.01 to 16.8), and mean age of participants treated in the control group was 6.4 years (range 0.05 to 16.7). Types of CVCs: 50 subcutaneous CVCs (27 in the experimental group and 23 in the control group), 94 exteriorised CVCs (45 in the experimental group and 49 in the control group), 38 percutaneous intravenous central catheters (19 in the experimental group and 19 in the control group). Type of CVC was unknown in four patients (one in the experimental group and three in the control group)

Underlying diseases: 94 cancer (47 in the experimental group and 47 in the control group), 42 congenital heart disease (23 in the experimental group and 19 in the control group), 15 systemic disease (seven in the experimental group and eight in the control group), 35 other (15 in the experimental group and 20 in the control group)


InterventionsReviparin-sodium, an LMWH (n = 92, experimental group) versus no intervention (n = 94, control group)

Participants in the experimental group received 30 IU/kg if ≥ 3 months of age or 50 IU/kg if < 3 months of LMWH (Knoll, Germany) twice daily. Participants in both treatment groups received standard catheter care: UFH flushes or very low dose infusion of UFH < 3 IU/kg/h


Outcomes
  • Asymptomatic CVC-related VTE, confirmed by an exit venogram at day 30 or at the time of CVC removal (14 days later). If venography was not possible, ultrasound was used for radiological assessment
  • Symptomatic VTE, any location, within 30 days of CVC placement
  • Adverse events: major or minor bleeding. Major bleeding was defined as clinically significant overt bleeding that required immediate transfusion of red blood cells, or any retroperitoneal, intracranial or intra-articular bleeding. Minor bleeding events were defined in the context of the primary underlying disorder and what was "usually" expected, such as, but not exclusive to: bruising or oozing around intravenous sites and surgical wounds; small amounts of blood derived from suctioning an endotracheal tube; small amounts of blood in the urine and stool; minor nose bleeds


Notes
  • The study was closed prematurely because of slow recruitment rates
  • The use of local thrombolytics should have been an outcome, because it can be a sign of (a)symptomatic VTE
  • CVC-related infections should have been an outcome because they coincide with CVC-related thrombosis


Follow-up of participants lasted for 30 days


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "They were randomly assigned by a computer-derived protocol"

Allocation concealment (selection bias)Low riskQuote: "They were randomly assigned by a computer-derived protocol"

Incomplete outcome data (attrition bias)
All outcomes
High risk28/186 participants were not evaluable for the primary efficacy analysis. For 23 participants, the mandatory venogram was not done, usually because of an inability of the participant to be transported to the radiology department. For the other five participants, the venograms were indeterminate

Selective reporting (reporting bias)Low riskComplete reporting for all outcome measures investigated

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study

Blinding of outcome assessment symptomatic VTE (detection bias)High riskQuote: "An independent and blinded Central Adjudication Committee assessed all efficacy and safety outcomes". However, as this study was open label and symptoms of symptomatic VTE were assessed by clinicians not blinded to the allocated treatment group, we assume a high risk of bias for this study

Blinding of outcome assessment asymptomatic VTE (detection bias)Low riskQuote: "An independent and blinded Central Adjudication Committee assessed all efficacy and safety outcomes"

Blinding of outcome assessment major bleeding, minor bleeding, thrombocytopenia, HIT, HITT, death due to (a)symptomatic VTE, removal of CVC because of (a)symptomatic VTE, CVC-related infection and CVC-related bacteraemia and/or post-thrombotic syndrome (detection bias)High riskMajor bleeding and minor bleeding were evaluated. Quote: "An independent and blinded Central Adjudication Committee assessed all efficacy and safety outcomes". However, as this study was open label and symptoms of major and minor bleeding were assessed by clinicians not blinded to the allocated treatment group, we assume a high risk of bias for this study


MethodsSingle-centre CCT conducted in Insbruck, Austria


Participants112 paediatric patients (> 12 months) with ALL, treated between June 1995 and January 2006. Types of CVCs were not mentioned


InterventionsEnoxaparin, an LMWH, and AT supplementation (n = 41, experimental group) versus AT supplementation (n = 71, control group)

LWMH was given subcutaneously every 24 hours during the induction and reinduction phases. LWMH was started with the first doses of CASP and was discontinued when AT levels resolved within 1 to 2 weeks after cessation of CASP. Doses of LMWH were weight adjusted (range 0.75 to 1.2 mg/kg BW). AT supplementation was given to all participants when the AT level fell by ≤ 50%. The amount of AT was calculated as follows: units required (IU) = (desired minus baseline AT levels) × weight (kg)/1.4, where baseline AT functional levels were expressed as percent of normal. Also, all participants received UFH flushes (100 IU/mL, up to tree times daily)


Outcomes
  • Symptomatic VTE, any location, defined as objectively documented VTE during the 240-day study period and confirmed by appropriate radiological tests. Participants with CVC-related VTE or VTE at the CVC tip with no symptoms of swelling, tenderness, pain or venous dilatation were considered asymptomatic and were not included in the study. However, CVC-related VTE with associated symptoms or those requiring removal or revision of the CVC were considered symptomatic and were included in the study. Right atrial thrombi detected on routine echocardiography without associated symptoms were excluded from analysis. Standard radiological methods, based on institutional guidelines, were used to confirm the diagnosis of VTE: magnetic resonance imaging for central VTE, Doppler ultrasonography and venography for deep venous thrombosis, ventilation-perfusion scan and/or spiral computed tomography for pulmonary embolism and echocardiography for right atrial thrombo-embolism
  • Adverse events: major and minor bleeding. Major bleeding was defined as intracranial, intra-abdominal or pulmonary bleeding episodes and those with a drop in haemoglobin needing prompt transfusion. Minor bleeding was defined as all bleeding episodes that were not major


NotesAT supplementation is not standard care currently. Therefore a true control group is missing

Follow-up of participants was 240 days


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskCCT; no randomisation performed

Allocation concealment (selection bias)High riskCCT; no randomisation performed

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber and reason for exclusion not specified

Selective reporting (reporting bias)Low riskComplete reporting for all outcome measures investigated

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of participants or personnel performed

Blinding of outcome assessment symptomatic VTE (detection bias)High riskNo blinding of outcome assessors performed

Blinding of outcome assessment major bleeding, minor bleeding, thrombocytopenia, HIT, HITT, death due to (a)symptomatic VTE, removal of CVC because of (a)symptomatic VTE, CVC-related infection and CVC-related bacteraemia and/or post-thrombotic syndrome (detection bias)High riskMajor bleeding and minor bleeding were evaluated; no blinding of outcome assessors was performed


MethodsMulti-national, multi-centre open-label RCT conducted in Canada and the USA


Participants109 paediatric patients with ALL, treated between July 1997 and May 1999. Types of CVCs were not mentioned


InterventionsAT supplementation (n = 37, experimental group) versus no intervention (n = 72, control group)

Median age of participants treated in the experimental group was 3.8 years (range 1.6 to 17.2), and median age of participants treated in the control group was 5.9 years (range 1.9 to 16.7). Participants in the experimental group were treated with AT (Thrombate III, Bayer Corporation, USA) once weekly for four weeks to increase plasma concentrations to 3.0 IU/mL, but no more than 3 IU/mL. The amount of AT required was calculated as follows: Units required = ((desired - baseline AT levels) × weight (kg))/1.4. All participants received standard catheter care: continuous infusion with UFH (1 to 3 IU/mL) or UFH flushes (50 to 100 IU/mL, maximum four times daily)


Outcomes
  • Symptomatic VTE, any location, was assessed by close monitoring of participants during the study period and was confirmed by appropriate objective radiographic tests. No definitions were stipulated for clinical presentation, which was left to the judgement of the attending physician
  • Asymptomatic VTE was assessed by radiographic testing after completion of the induction phases of chemotherapy. During the follow-up period (day 28 to a further three months), all participants were screened with radiographic tests consisting of: bilateral venography or magnetic resonance imaging of the upper body, ultrasound of the upper body, an echocardiogram and magnetic resonance imaging of the head
  • Adverse events: major and minor bleeding. Major bleeding was defined as overt bleeding requiring transfusion of red blood cells or any bleed in the central nervous system or the retroperitoneum. Minor bleeding was defined as any bleeding not considered major


NotesThe study was powered to detect a trend

A quarter of the AT supplemented patients had plasma levels fall below normal, most likely as a result of the dosing schedule

Follow-up of participants lasted for 3 months


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were block randomised by hospital and stratified by ALL risk group (high or standard). Randomisation was performed by the pharmacist-on-call using a computer-generated random number list"

Allocation concealment (selection bias)Low riskQuote: "Randomisation was performed by the pharmacist-on-call using a computer-generated random number list"

Incomplete outcome data (attrition bias)
All outcomes
High risk24 participants were excluded from the analysis, 12 (17%) in the non-AT-treated group and 12 (32%) in the AT-treated group

Selective reporting (reporting bias)Low riskComplete reporting for all outcome measures investigated

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label

Blinding of outcome assessment symptomatic VTE (detection bias)High riskNo blinding of outcome assessors performed

Blinding of outcome assessment asymptomatic VTE (detection bias)Low riskQuote: "All radiographic tests were assessed for the presence or absence of thrombosis by a central adjudication committee, which consisted of physicians with appropriate expertise who were not involved in the patient's care, and who were blinded to treatment groups"

Blinding of outcome assessment major bleeding, minor bleeding, thrombocytopenia, HIT, HITT, death due to (a)symptomatic VTE, removal of CVC because of (a)symptomatic VTE, CVC-related infection and CVC-related bacteraemia and/or post-thrombotic syndrome (detection bias)High riskMajor bleeding and minor bleeding were evaluated; no blinding of outcome assessors was performed


MethodsOpen-label RCT conducted in two centres in Norway


Participants73 paediatric oncology patients, treated between January 2002 and October 2003, were randomly assigned. Eleven participants were excluded from the analyses. Mean age of participants treated in the experimental group was 7.3 years, and mean age of participants treated in the control group was 6.2 years. Types of CVCs: 38 single lumen (16 in the experimental group and 22 in the control group), 10 double lumen (six in the experimental group and four in the control group) and 14 port (seven in the experimental group and seven in the control group)

Underlying diseases: 29 ALL (14 in the experimental group and 15 in the control group), six AML (four in the experimental group and two in the control group), seven brain tumour (three in the experimental group and four in the control group), five lymphoma (two in the experimental group and three in the control group) and 15 other solid tumours (six in the experimental group and nine in the control group)


InterventionsWarfarin (n = 31, experimental group) versus no intervention (n = 42, control group)

Participants in the experimental group were treated with warfarin (Marevan, Nycome Pharma, Norway) for six months with an intended INR between 1.3 and 1.9. Participants were started on warfarin (0.1 mg/kg) on the same day that their CVCs were inserted


Outcomes
  • Symptomatic CVC-related VTE, confirmed by ultrasonography of the central neck veins
  • Asymptomatic CVC-related VTE, assessed by ultrasonography of the central neck veins at one, three and six months after inclusion
  • Adverse events: major bleeding, defined as intracerebral or intra-abdominal haemorrhages or a fall in haemoglobin greater than 2 g/dL


NotesSubtherapeutic doses of warfarin

Follow-up of participants was 6 months


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The randomisation was practically organised by the principal investigator by drawing closed envelopes from boxes. There were two boxes of envelopes: one for children for whom treatment with asparaginase was planned, and one for those who were not intended to receive asparaginase"

Allocation concealment (selection bias)Low riskQuote: "The randomisation was practically organised by the principal investigator by drawing closed envelopes from boxes. There were two boxes of envelopes: one for children for whom treatment with asparaginase was planned, and one for those who were not intended to receive asparaginase"

Incomplete outcome data (attrition bias)
All outcomes
High risk11 participants were excluded after randomisation: two in the experimental group and nine in the control group. Reasons for exclusion were: death (n = 3), removal of CVC before 6 months (n = 2), VTE in need forof antithrombotic treatment (n = 2), withdrawal (n = 2), prophylactic anticoagulation after major orthopaedic surgery (n = 1) and interaction with other drugs (n = 1)

Selective reporting (reporting bias)Low riskComplete reporting for all outcome measures investigated

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study

Blinding of outcome assessment symptomatic VTE (detection bias)High riskNo blinding of outcome assessors was performed

Blinding of outcome assessment asymptomatic VTE (detection bias)Low riskQuote: "The radiologists who performed the ultrasonography were blinded to the treatment assignment, and, unless the child had symptoms of VTE, results from the scheduled ultrasonographies were not available for clinicians"

Blinding of outcome assessment major bleeding, minor bleeding, thrombocytopenia, HIT, HITT, death due to (a)symptomatic VTE, removal of CVC because of (a)symptomatic VTE, CVC-related infection and CVC-related bacteraemia and/or post-thrombotic syndrome (detection bias)High riskThe following secondary outcomes were evaluated: major bleeding. No blinding of outcome assessors was performed

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Abdelkefi 2000(1) Observational study of CVC-related complications

(2) No investigation of systemic treatments to prevent VTE

Abdelkefi 2004(1) Non tunnelled CVC

(2) Prophylaxis not systemic

Abdelkefi 2008(1) Adult study population

(2) Prophylaxis not systemic; coated CVCs

Akl 2007(1) Study population consisted mainly of adults

(2) Cochrane review

Andrew 1995(1) Children with malignancies were not included in this study

(2) Observational study of CVC related thrombosis

(3) No investigation of systemic treatments to prevent VTE

Athale 2009Observational study of the impact of CVC dysfunction on survival

Athale 2010(1) Treatment of thrombotic events

(2) Observational study of management of thromboembolism

Athale 2012Observational study of the impact of central venous line dysfunction on the outcome of children with cancer

Bagnall 1989(1) Treatment of thrombotic events

(2) Treatment not systemic

Barzaghi 1995Observational study of CVC-related clots in patients with haematologic malignancies

Bohlin 2009Adult study population

Buller 2007(1) Treatment of thrombotic events

(2) Adult study population

Carrier 2007Review of thromboprophylaxis for CVC related thrombosis in adult cancer patients

Cesaro 2002(1) Treatment of thrombotic events

(2) Case report

Cesaro 2002aLetter to the editor

Cesaro 2009Prophylaxis not systemic

Chatzinikolaou 2003Prophylaxis not systemic

Coleman 2009(1) Adult study population

(2) Observational study of predictors of deep vein thrombosis

Cortelezzi 2003Prophylaxis not systemic

Couban 2005Adult study population1

Davenport 2010Study population consisted of patients with non-malignant diseases

De Cicco 2006Adult study population

Deady 2010(1) Treatment of thrombotic events

(2) Review of thrombotic events in children receiving asparaginase

Dillon 2004Treatment not systemic

Dümichen 2012Prophylaxis not systemic

Eichinger 2008(1) Adult study population

(2) Prophylaxis not systemic

Fagnani 2006Adult study population

Faranoush 2007Observational study of thrombotic risk factors in ALL patients without CVCs

Farge 2008Guideline

Farhan 2008Adult study population

Farinasso 2007Observational study of thrombotic risk factors in ALL patients

Ferreira Chacon 2011Prophylaxis not systemic

Fratino 2005(1) Observational study of CVC related complications

(2) No investigation of systemic treatments to prevent VTE

Freytes 2003Review of CVC related complications

Gabrail 2009(1) Study population consisted mainly of adult patients

(2) Treatment of thrombotic events

Gerotziafas 2004Review of risk factors for thrombotic events in children

Giordano 2007Guideline for diagnosis and treatment of thrombotic events

Goldenburg 2009Observational study of the post thrombotic syndrome and scale validation

Goldenburg 2009aReview of post thrombotic syndrome

Gonzalez 2010(1) Observational study of CVC-related complications

(2) No investigation of systemic treatments to prevent VTE

Halton 2012(1) Study protocol

(2) Observational study investigating the correlation between CVL dysfunction and symptomatic thromboembolism

Harney 2010Observational study monitoring the initiation of prophylactic anticoagulation therapy and diagnosis of DVT

Henrickson 2000(1) Prophylaxis not systemic

(2) Prevention of CVC related infections

Hoppensteadt 2008Animal model

Kakkar 2009Adult study population

Kalmanti 2002Prophylaxis not systemic

Kayton 2010Prophylaxis not systemic

Kefeli 2009(1) Patient population consisted mainly of adults

(2) Prophylaxis not systemic

Kenney 1996Treatment of thrombotic events

Kethireddy 2008Prophylaxis not systemic

Kovacs 2006(1) Adult study population

(2) Treatment of thrombotic events

Kuhle 2008Observational study of the post thrombotic syndrome in childhood cancer survivors

Lee 2009Adult study population

Levine 2009Adult study population

Malowany 2008(1) Children with malignancies were not included in this study

(2) Review

(3) Treatment of thrombotic events in neonates

Masroujeh 2008(1) Adult study population

(2) Patients with malignancies were not included in this study

(3) Observational study of the use of venous thromboembolism prophylaxis

Massicotte 2003aDose-finding study

Massicotte 2006Review on thromboprophylaxis of CVC related thrombotic events

Molinari 2004Treatment blocked central venous catheters

Möricke 2009(1) Observational study of thrombotic events

(2) No investigation of systemic treatments to prevent VTE

Nguyen 2008Adult study population

Odabas 2010(1) Adult study population

(2) Prophylaxis not systemic

Ragni 2008Haemophilia patients

Riess 2009Adult study population

Rodenhuis 1993Treatment of thrombotic events

Ruud 2006aObservation study of the thrombotic effects of asparaginase

Savage 1999(1) Treatment of thrombotic events

(2) Adult study population

Schiavetti 2006(1) Observational study of CVC-related thrombosis

(2) No investigation of systemic treatments to prevent VTE

Sharathkumar 2010Observational study of the post thrombotic syndrome and scale validation

Simmons 2011(1) Adult study population

(2) Review of the risk/benefit ratio of LMWH to reduce the risk of thrombotic events

Simon 2008(1) Prophylaxis not systemic

(2) Review of the use of urokinase in the prevention and management of CVAD-related complications in paediatric oncology patients

Simons 2010Adult study population

Skinner 2008Survey on prevention and management of CVC-related thrombosis

Smith 1991Prophylaxis not systemic

Tassinari 2007Review of the role of LMWH as prophylaxis of CVC-related thrombosis

Terrill 2003Treatment of thrombotic events

Tesselaar 2004(1) Patient population consisted mainly of adults

(2) Observational study of risk factors for CVC-related thrombotic events

Traby 2009(1) Adult study population

(2) Dose finding study

Trame 2009Investigates pharmacokinetics of enoxaparin in children

Van Leeuwen 2009(1) Adult study population

(2) Treatment of thrombotic events

Verso 2009Adult study population

Verso 2009aAdult study population

Yamashita 2009Investigates the safety of anti-thrombin supplementation

Young 2007Non oncology patients

Young 2009Treatment of thrombotic events

 
Comparison 1. Systemic preventive treatment versus no intervention, symptomatic VTE

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Meta-analysis2Risk Ratio (M-H, Random, 95% CI)Subtotals only

   1.1 Best case scenario
2182Risk Ratio (M-H, Random, 95% CI)0.65 [0.09, 4.78]

   1.2 As treated analysis
2147Risk Ratio (M-H, Random, 95% CI)0.64 [0.09, 4.74]

 2 Massicotte 20031Risk Ratio (M-H, Random, 95% CI)Subtotals only

   2.1 Best case scenario
1186Risk Ratio (M-H, Random, 95% CI)1.02 [0.21, 4.93]

   2.2 As treated analysis
1158Risk Ratio (M-H, Random, 95% CI)1.03 [0.21, 4.93]

 
Comparison 2. Systemic preventive treatment versus no intervention, asymptomatic VTE and symptomatic VTE

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Meta-analysis2Risk Ratio (M-H, Random, 95% CI)Subtotals only

   1.1 Best case scenario
2182Risk Ratio (M-H, Random, 95% CI)1.02 [0.40, 2.55]

   1.2 As treated analysis
2147Risk Ratio (M-H, Random, 95% CI)1.05 [0.62, 1.78]

 2 Massicotte 20031Risk Ratio (M-H, Random, 95% CI)Subtotals only

   2.1 Best case scenario
1186Risk Ratio (M-H, Random, 95% CI)1.12 [0.50, 2.52]

   2.2 As treated analysis
1158Risk Ratio (M-H, Random, 95% CI)1.13 [0.51, 2.50]

 
Comparison 3. Systemic preventive treatment versus no intervention, major bleeding

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Meta-analysis2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   1.1 Best case scenario
2182Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.05, 3.31]

   1.2 As treated analysis
2147Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.05, 3.08]

 
Comparison 4. Systemic preventive treatment versus no intervention, minor bleeding

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Massicotte 20031Risk Ratio (M-H, Random, 95% CI)Subtotals only

   1.1 Best case scenario
1186Risk Ratio (M-H, Random, 95% CI)1.20 [0.88, 1.62]

   1.2 As treated analysis
1184Risk Ratio (M-H, Random, 95% CI)1.22 [0.91, 1.65]

 
Table 1. Cohort studies

StudyPatientsInterventionsOutcomes

Harlev 201018 paediatric oncology patients with ALL and a genetic predisposition for VTELMWH prophylaxis:

18 participants were found to harbour a genetic predisposition for VTE (heterozygosity for prothrombin gene mutation (n = 6), heterozygosity for factor V Leiden mutation (n = 12)) and received LMWH prophylaxis. Enoxaparin was administered 1 dd, 1 mg/kg, subcutaneously
3/18 participants receiving prophylaxis developed a CVC-related VTE: two symptomatic and one asymptomatic (discovered by cardiac ultrasound)

 

Adverse events or episodes of bleeding were not reported

Mitchell 20108 paediatric oncology patients with ALL and increased risk of VTELMWH prophylaxis:

All participants with increased risk of VTE were eligible for enoxaparin prophylaxis. 8/19 participants with increased risk of VTE received enoxaparin prophylaxis. The remaining 11 participants refused study participationa 

Enoxaparin was administered 1 dd, 1 mg/kg
1/8 participants receiving prophylaxis developed a symptomatic VTE

No episodes of bleeding occurred. Adverse events were not reported

Zaunschirm 198613 paediatric oncology patients with ALLFFP and/or AT III supplementation:

Fibrinogen and AT III were determined every 2 to 3 days. FFP was administered if fibrinogen < 100 mg/dL, the amount calculated to raise fibrinogen levels to at least 120 mg/dL. FFP was given 3 dd. AT III was administered if AT III < 80% of normal but fibrinogen > 100 mg/dL, calculated to raise AT III levels to > 100% of normal (1 U/kg raises the level by 1%). AT III was given as a continuous infusion
0/10 participants receiving FFP supplementation developed VTE

0/13 participants receiving AT III supplementation developed VTE

One participant receiving FFP and AT III was diagnosed with disseminated intravascular coagulation preceding supplementation

No episodes of bleeding or adverse events occurred 

Brasseur 200724 paediatric oncology patients with ALLFFP supplementation:

Fresh frozen plasma (FFP) was administered on alternate days (mean 11.5 ± 0.9 mL/kg).
1/24 participants developed a VTE of the superior longitudinal sinus with ischaemo-haemorrhagic stroke. No other episodes of bleeding were reported

Adverse events were not reported

 ALL: acute lymphoblastic leukaemia; AT: antithrombin; CVC: central venous catheter; FFP: fresh frozen plasma; LMWH: low molecular weight heparin; VTE: venous thrombo-embolic event.
Be aware: These studies cannot be used to evaluate the efficacy of prevention but can be used for the description of safety. The quality of cohort studies is considered by The Cochrane Collaboration to be too low for efficacy analyses (Higgins 2011).
aObtained from personal communication with the author.
 
Table 2. Fisher's exact test of outcomes with no events in the experimental or control group

Studya InterventionExperimental group (n)Control group (n)Outcome*Events (experimental)Events (control)Two-sided P value

Systemic preventive treatment versus no intervention

Elhasid (ITT)LMWH versus no intervention4150Symptomatic VTE011.00

Abbott (ITT)FFP and/or CRY supplementation versus no intervention240479Symptomatic VTE070.10

Massicotte

(best case scenario)
LMWH versus no intervention9294Major bleeding011.00

Massicotte

(as treated)
LMWH versus no intervention7880Major bleeding011.00

Mitchell (best case scenario)AT versus no intervention3772Minor bleeding200.12

Mitchell (as treated)AT versus no intervention2560Minor bleeding200.094

Systemic preventive treatment versus other systemic treatment

Meister (unclear whether ITT or best case scenario)AT + LMWH versus AT4171Symptomatic VTE090.028

 ITT: intention to treat; LMWH: low molecular weight heparin; AT: antithrombin; CRY: cryoprecipitate; VTE: venous thrombo-embolic event
aThe definitions used in the different studies can be found in the table of included studies (Characteristics of included studies).