Low molecular weight heparin for prevention of central venous catheterization-related thrombosis in children.

Low molecular weight heparin for prevention of central venous catheterization-related thrombosis in children (Review) Brandão LR, Shah N, Shah PS

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 3 http://www.thecochranelibrary.com

Low molecular weight heparin for prevention of central venous catheterization-related thrombosis in children (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 LMWH versus standard care for CVC: thrombosis, Outcome 1 Symptomatic thrombosis. Analysis 1.2. Comparison 1 LMWH versus standard care for CVC: thrombosis, Outcome 2 Asymptomatic thrombosis. Analysis 2.1. Comparison 2 LMWH versus standard care for CVC: bleeding events, Outcome 1 Major bleeding. . . Analysis 2.2. Comparison 2 LMWH versus standard care for CVC: bleeding events, Outcome 2 Minor bleeding. . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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[Intervention Review]

Low molecular weight heparin for prevention of central venous catheterization-related thrombosis in children Leonardo R Brandão1 , Niketa Shah2 , Prakeshkumar S Shah3 1 Division of Haematology-Oncology, The Hospital for Sick Children, Toronto, Canada. 2 Department of Pediatrics, New Jersey Hospital, Jersey City, New Jersey, USA. 3 Department of Paediatrics and Health Policy, Management and Evaluation, University of Toronto Mount Sinai Hospital, Toronto, Canada

Contact address: Leonardo R Brandão, Division of Haematology-Oncology, The Hospital for Sick Children, 555 University Avenue, Black Wing, room 10412, Toronto, Ontario, M5G-1X8, Canada. [email protected]. Editorial group: Cochrane Peripheral Vascular Diseases Group. Publication status and date: New, published in Issue 3, 2014. Review content assessed as up-to-date: 11 June 2013. Citation: Brandão LR, Shah N, Shah PS. Low molecular weight heparin for prevention of central venous catheterization-related thrombosis in children. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD005982. DOI: 10.1002/14651858.CD005982.pub2. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background The prevalence of children diagnosed with deep vein thrombosis or pulmonary embolism has been increasing in the last decade. The most common thrombosis risk factor in neonates, infants and children is the placement of a central venous catheter (CVC). To date, it is unknown if the practice of anticoagulation prophylaxis with low molecular weight heparin (LMWH) decreases CVC-related thrombosis in children. Objectives The primary objective of this review was to determine the effect of LMWH prophylaxis on reducing the incidence of CVC-related thrombosis in children. Secondary objectives were to determine the effect of LMWH on occlusion of CVCs, number of days of CVC patency, episodes of catheter-related sepsis, side effects of LMWH (allergic reactions, major and minor bleeding complications, abnormal coagulation profile, osteoporosis) and mortality during therapy. Search methods The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched June 2013), CENTRAL (2013, Issue 5) and clinical trial databases. The authors searched MEDLINE and EMBASE (July 2013). Bibliographies of identified articles were searched. There were no language restrictions. Selection criteria Randomised and quasi-randomised trials comparing LMWH prophylaxis to standard care given to prevent CVC-related thrombotic events in children were included. We selected studies conducted in children aged 0 to 18 years. Data collection and analysis Two review authors independently identified eligible studies, which were assessed for study quality including bias, and extracted unadjusted data where available. In the data analysis step, all outcomes were analysed as binary or dichotomous outcomes. The effects of interventions were summarised with risk ratios (RR) and their respective 95% confidence intervals (CI). Low molecular weight heparin for prevention of central venous catheterization-related thrombosis in children (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Main results One of 17 studies retrieved for full-text assessment for eligibility was included in the final analysis. This study included a total of 186 participants and investigated the effect of LMWH to prevent CVC-related thrombosis compared to standard care. The risk of bias of the study was assessed to be low, except for the unclear risk of selection bias (allocation concealment not reported) and detection bias since it was an open-label study. Nonetheless, outcome adjudication was blinded. However, overall the quality of the evidence was low due to the fact that the study was underpowered. The CIs for the risk of CVC-related thrombosis (symptomatic and asymptomatic events) were compatible with benefits of either LMWH (reviparin) or the control (RR for symptomatic thrombosis 1.03, 95% CI 0.21 to 4.93; RR for asymptomatic thrombosis 1.17, 95% CI 0.45 to 3.08). Similarly, only one patient in the standard care group suffered a major bleeding event, while minor bleeding was found in 53.3% of patients in the reviparin arm and in 44.7% of patients in the standard care arm (major bleeding RR 0.34, 95% CI 0.01 to 8.26; minor bleeding RR 1.20, 95% CI 0.91 to 1.58). Lastly, there were two deaths within the study and neither were the result of a venous thrombotic event (VTE), occurring in the standard care arm. No additional adverse effects were reported. Other pre-specified outcomes for this review were not reported. Authors’ conclusions A single study reported imprecise effects for the risk of CVC-related thrombosis in children on a CVC anticoagulant prophylaxis regimen. The quality of the evidence was low due to the fact that the included study was clearly underpowered, hampering any conclusions in regards to the efficacy of LMWH prophylaxis to prevent CVC-related thrombi in children. Further prospective randomised studies are highly encouraged.

PLAIN LANGUAGE SUMMARY Blood thinners for the prevention of blood clots in children with central venous lines Over the last 10 years, the number of children found to have blood clots in their blood vessels, called veins, has become more common. As blood clots can either block these vessels and change their normal blood flow or shower pieces into other veins placed in important organs, serious health problems including death can occur. Venous clots are usually found in children with plastic tubes placed inside their blood vessels, called central lines, which are inserted to help or save the patient’s life. However, these lines can also cause blood clots. We do not know if giving a medication to protect against blood clots, called an anticoagulant or low molecular weight heparin (LMWH), would protect against the clots. Therefore, we looked at all the research in children with central lines who received, or not, LMWH and only found one study with a total of 186 participants. This study did not have enough participants to show if this medication protects children with central lines from getting blood clots. The study also did not show that children on LMWH, at the doses given, experience too much bleeding because of its use. The included study did not report any additional adverse events. There were two deaths within the study in the standard care arm, and neither were due to a blood clot. Future studies looking at the role of this medication (LMWH) and if it protects children with central venous lines from getting blood clots are needed.


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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Low molecular weight heparin for prevention of central venous catheter (CVC)-related thrombosis in children Patient or population: Children with central venous catheter Settings: Paediatric tertiary hospital Intervention: Low molecular weight heparin Comparison: Control (placebo, no treatment or standard of care for central venous catheter (unfractionated heparin (UFH) flushes or low dose UFH) Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

Control

Low molecular weight heparin

CVC-related symptomatic Study population thrombosis 38 per 1000 Venography §

Relative effect (95% CI)

No of participants (studies)

Quality of the evidence (GRADE)

RR 1.03 (0.21 to 4.93)

158 (1 study)

low# ⊕⊕

RR 1.17 (0.45 to 3.48)

158 (1 study)

low# ⊕⊕

39 per 1000 (8 to 185)

Low risk population 75 per 1000

CVC-related asymptomatic Study population thrombosis 88 per 1000 Venography §

77 per 1000 (16 to 370)

102 per 1000 (30 to 305)

Moderate risk population 300 per 1000

351 per 1000 (135 to 1000)

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Side effects of LMWH: major Study population bleeding 11 per 1000 Clinical findings

RR 0.34 (0.01 to 8.26)

184 (1 study)

low# ⊕⊕

RR 1.2 (0.91 to 1.58)

184 (1 study)

low# ⊕⊕

Not estimable

184 (1 study)

low# ⊕⊕

4 per 1000 (0 to 88)


Side effects of LMWH: minor Study population bleeding 436 per 1000 Clinical findings

3 per 1000 (0 to 83)

523 per 1000 (397 to 689)


Mortality during period of Study population therapy See commentˆ

360 per 1000 (273 to 474)

See commentˆ

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) § Follow up for less than five to more than 30 days # Underpowered study; study was closed prematurely due to slow recruitment rate ˆ There were 2 deaths during the study period, both were unrelated to thrombosis and occurred in the standard of care arm CI: Confidence interval; RR: Risk Ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

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BACKGROUND

Description of the condition Indwelling central venous catheters (CVCs) were introduced by Broviac et al in 1973 for parenteral alimentation, in hospital or at home (Broviac 1973). Later, Hickman et al modified the catheter size and used the catheter for stem cell transplant patients (Hickman 1979). Since then, CVCs have been widely used for a variety of indications such as monitoring of haemodynamic status and the administration of parenteral nutrition, blood products and chemotherapeutic agents, or the infusion of other fluids (Klerk 2003). Although advantageous, and at times life saving, the use of CVCs is associated with mechanical and infectious complications. The major mechanical complications observed are occlusion (blockage) and thrombosis (clotting) of the catheter (Bagnall-Reeb 1990; Bona 2003; Finkelstein 2004; Klerk 2003; Male 2003; Steele 2001; Vidler 1999). The exact incidence of catheter-related thrombosis is unknown but the estimated incidence is 4% to 66% (Andrew 1995; Fratino 2005; Krafte-Jacobs 1995). Several factors have been implicated in causing CVC-related thrombosis. These include underlying disease, for example, malignancies; the nature of the substances administered, such as chemotherapeutic agents or hyperosmolar solutions that can cause damage to the vascular endothelium; the site of the catheter, with a higher risk in femoral catheters than those inserted in jugular or subclavian veins (Klerk 2003); and the type of catheter (Carde 1989; Mclean 2005). The thrombosis related to CVCs can lead to pulmonary embolism, sepsis, stroke or post-thrombotic syndrome (Anton 2001) and may require long-term anticoagulants.

LMWH, an anticoagulant drug from the family of heparinoids available in several formulations, has been successfully used as a prophylactic regimen for CVCs in adults (Monreal 1996). For example, at a dose of 2500 IU daily given subcutaneously, the LMWH named dalteparin proved to be effective and safe in preventing the development of CVC-related deep venous thrombosis in adult cancer patients. The incidence of venography-proven thrombosis was 6% in the prophylaxis group versus 62% in the placebo group (relative risk (RR) 6.75, 95% confidence interval (CI) 1.05 to 43.58; P = 0.002) and no bleeding complications developed (Monreal 1996).

Why it is important to do this review The prophylactic use of LMWH for CVC-related thrombosis has not been evaluated in children in a systematic manner. The aim of this review was to evaluate the benefits and risks of LMWH for the prevention of CVC-related thrombosis in children.

OBJECTIVES The primary objective of this review was to determine the effect of LMWH prophylaxis on reducing the incidence of CVC-related thrombosis in children. Secondary objectives were to determine the effect of LMWH on: (1) occlusion of CVCs; (2) number of days of CVC patency; (3) episodes of catheter-related sepsis;

Description of the intervention The use of anticoagulation prophylaxis to avoid CVC-related thrombosis is a matter of debate in the paediatric population; the best method is not known. Unfractionated heparin (administered intermittently or as a continuous infusion) has been evaluated for the prevention of thrombotic complications in a few paediatric studies (Randolph 1998; Shah 2008). However, the benefits of using unfractionated heparin (UFH) have to be weighted against the risks of allergic reactions, heparin-induced thrombocytopenia (HIT) and bleeding complications secondary to errors in the dosage. On the other hand, low molecular weight heparin (LMWH) has the advantages of having a longer half-life, increased bioavailability, ease of administration and capability for careful monitoring in children (Anton 2001; Monagle 2012).

How the intervention might work

(4) side effects of LMWH (allergic reactions, major and minor bleeding complications, abnormal coagulation profile, osteoporosis); (5) mortality during therapy.

METHODS

Criteria for considering studies for this review

Types of studies We included randomised controlled trials of LMWH in children with CVCs and also studies that used alternative methods of randomisation such as alternate days of the week, odd or even date of birth, or hospital number (quasi-randomised). We did not include studies that used historical controls. For any studies in which the


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unit of randomisation was the catheter, we planned to contact the primary authors to obtain data for the first catheter after randomisation, but this was not required. If in future updates this is required and study authors are unable to provide the data or cannot be contacted, we shall describe the study and include only data on long-term outcomes such as osteoporosis, bleeding complications or mortality. Types of participants Children (age one month to 18 years) who required CVCs during their course of treatment either while in hospital or after discharge. The trial participants must have received LMWH versus control (placebo, no treatment, or UFH) without restriction to the specific dose. LMWH, placebo or UFH must have been administered during the entire time the catheter was in place.

3. Episodes of CVC-related sepsis (children with one or more episode). CVC-related sepsis was defined as symptoms and signs suggestive of sepsis accompanied by positive blood cultures obtained from a normally sterile site different to a central line, and from the line or catheter tip, each growing the same micro-organism. 4. Side effects of LMWH (allergic reactions, major and minor bleeding complications, abnormal coagulation profile, osteoporosis). 5. Mortality during the period of therapy. 6. Any other reported adverse outcomes (not pre-specified).

Search methods for identification of studies There were no restrictions on language.

Types of interventions LMWH versus control interventions (CVCs without prophylactic heparin, or CVCs with prophylactic UFH) without restrictions on the dose of heparin. Types of outcome measures Studies that reported on one or more of the following outcomes amongst the randomised participants. Primary outcomes

CVC-related thrombosis (along the length of, or at the tip of, the catheter) as determined by either colour duplex Doppler ultrasonography or contrast venography, with or without clinical suspicion. This was determined as dichotomous data (yes or no). We intended to obtain the time durations of development of catheterrelated thrombosis as follows: • within one week of catheter placement; • within two weeks of catheter placement; • within four weeks of catheter placement; • after four weeks of catheter placement. CVC-related thrombosis could be symptomatic or asymptomatic. Secondary outcomes

1. Occlusion of the catheter (defined as inability to infuse fluids through the catheter due to blockage). This was determined as dichotomous data (yes or no). We intended to obtain the time durations of development of occlusion of the catheter as follows: (a) within one week of catheter placement; (b) within two weeks of catheter placement; (c) within four weeks of catheter placement; (d) after four weeks of catheter placement. 2. Days of catheter patency (duration of patency of first catheter, in days).

Electronic searches The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched June 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 5), part of The Cochrane Library (www.thecochranelibrary.com). See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases Group module in The Cochrane Library ( www.thecochranelibrary.com). The following trial databases were searched by the TSC for details of ongoing and unpublished studies using the terms catheter and thrombosis and heparin: • World Health Organization International Clinical Trials Registry (http://apps.who.int/trialsearch/); • ClinicalTrials.gov (http://clinicaltrials.gov/); • Current Controlled Trials (http://www.controlledtrials.com/).

Authors’ searches

We searched MEDLINE (1946 to week 1 July 2013) and EMBASE (1980 to 2013 Week 27). The search strategies can be found in Appendix 2 and Appendix 3.

Searching other resources In addition, we searched the reference lists of identified trials.


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Data collection and analysis

Selection of studies Two review authors independently assessed all published articles identified as potentially relevant by the literature search for inclusion in the review. In order to be included, the trial had to meet the following criteria: • the study population were children (age one month to 18 years); • the intervention was LMWH compared with placebo, no treatment or UFH for CVCs; • the study was a randomised or quasi-randomised controlled trial; • one or more primary or secondary outcome measures were reported.

Assessment of heterogeneity The Chi2 test of homogeneity, with the significance threshold set at P < 0.10, was planned to be used to detect statistically significant heterogeneity. In addition, we intended to investigate the degree of heterogeneity by calculating the I2 statistic. Assessment of reporting biases We planned to investigate publication bias using funnel plots if 10 or more studies were identified. Data synthesis We utilised Review Manager software (RevMan 5.1) to perform data analysis. Statistical methods, where appropriate and data were available, included calculation of risk ratio (RR), risk difference (RD), number needed to treat (NNT) and mean difference (MD). We used 95% confidence intervals (CI) for these estimates of treatment effects. We used a fixed-effect model method based on the inverse variance approach for the analysis.

Data extraction and management Two of the review authors (LB, NS) independently extracted data from the retrieved articles. We contacted the primary authors of any articles for which there was inadequate information, or where relevant data could not be abstracted. Discrepancies were resolved by consensus.

Subgroup analysis and investigation of heterogeneity Given the limited number of studies retrieved, no subgroup analysis was carried out. If sufficient numbers of studies were available we planned to perform the following subgroup analyses according to the control intervention: 1. LMWH versus placebo, or no treatment; 2. LMWH versus unfractionated heparin.

Assessment of risk of bias in included studies The risk of bias of the included study was assessed as per the Cochrane risk of bias tool (Higgins 2008). Two review authors independently performed this evaluation (LB, NS) and discussed disagreements to reach a consensus.

Sensitivity analysis Given the limited number of studies retrieved, no sensitivity analysis was carried out. If in future updates sufficient studies are included we plan to perform a sensitivity analysis to assess the impact of low quality studies on the effects of the intervention by excluding them from the analysis.

Measures of treatment effect Pre-specified primary and secondary objectives were analysed as dichotomous or continuous outcomes, where relevant and when data were available.

Summary of findings table We used the principles of the GRADE system (Guyatt 2008) to assess the quality of the body of evidence associated with the outcomes in our review and constructed a ’Summary of findings’ (SoF) table using the GRADE software.

Unit of analysis issues No issues related to unit of analysis in the trial design were found since only the parallel group design was encountered.

RESULTS

Dealing with missing data

Description of studies

No imputation for missing data was required.

See Figure 1.


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Figure 1. Study flow diagram.


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Results of the search We retrieved a total of 1487 references from databases, registers and handsearching. All references were saved in an EndNote X6 library, which was used to identify 87 duplicates. One of the review authors (LB) reviewed the remaining 1400 references to check whether they met the inclusion criteria for this review. Twenty-one full-text articles were retrieved for assessment; only one of those 21 articles met the inclusion criteria for this review.

Included studies See Characteristics of included studies. One study met the eligibility criteria for this review (Massicotte 2003). This peer-reviewed manuscript included 186 children randomised to receive either LMWH (reviparin) prophylaxis (mean age 6.1 yr, standard deviation (SD) 5.2 yr) or standard care (mean age 6.4 yr, SD 5.0 yr) for prevention of CVC-related thrombosis (symptomatic or asymptomatic, or both) or thrombosis-related death. Additionally, the most common and relevant complication related to LMWH use, bleeding, was analysed between study arms. The inclusion criteria were neonates, infants and children with a newly placed CVC that were subsequently screened by examination or by imaging at CVC removal (that is day + 30). During CVC placement, patients randomised to the intervention arm received an age-appropriate LMWH dose to prevent thrombosis development. Alternatively, patients randomised to the standard care arm received heparin flushes or heparin infusions at low rates (not equivalent to systemic anticoagulation), a widespread clinical practice to ensure central line patency. The distribution of patients upon randomisation was very clear. The outcomes reported were the rate of CVC-related thrombosis in both arms within 30 days of CVC placement or at the time of CVC removal (+ 14 days if < 30 days).

Excluded studies See Characteristics of excluded studies. A total of 20 full-text articles were excluded or deemed not relevant for this review. A total of 16 studies (16 full-text articles) were excluded for the following reasons: trials run in the adult care setting (Abdelkefi 2004; De Cicco 2009; Karthaus 2006; Mismetti 2003; Monreal 1996; Niers 2007; Verso 2005); prospective cohort studies (Mitchell 2010; Raffini 2011; Trame 2010); retrospective cohort studies (Cavo 2010; Harlev 2010; Harney 2010; Sandoval 2008; van Ommen 2010) and mixed design (Vegting 2012). A further four full-text articles were deemed not relevant as they were either a review or editorial on the topic. From the 16 excluded studies, three studies merited a closer look (Harlev 2010; Mitchell 2010; Vegting 2012). They were reports

from two single institution studies (Harlev 2010; Vegting 2012) and from one multicentre collaborative study (Mitchell 2010). The studies by Harlev (Harlev 2010) and Mitchell (Mitchell 2010) analysed the incidence of thrombosis in children with the most common form of paediatric cancer, acute lymphoblastic leukaemia (ALL), which is also one of the most common underlying conditions associated with paediatric thrombosis. Interestingly, both studies followed the same chemotherapy protocol, which is one of the considered relevant prothrombotic risk factors in children diagnosed with ALL, allowing comparison of their results. The study by Harlev (Harlev 2010) was a peer-reviewed publication including children treated over a nine-year period (1999 to 2008); their overall thrombosis incidence was 7.5%, and patients carrying an inherited thrombotic risk factor (that is thrombophilia (factor V Leiden or prothrombin gene mutation)) received upfront LMWH prophylaxis (enoxaparin 1 mg/kg/dose, x 1 day) during the most thrombogenic phases of their chemotherapy protocol. The group with thrombophilia and LMWH had a thrombosis incidence of 16.6%, much lower than the previous historical report in the same subpopulation but without LMWH (~ 47%) (Nowak-Göttl 1999). The incidence in the low risk patients was 4.5% (Harlev 2010). Half of those thrombotic events occurred in patients with CVCs. The study by Mitchell (Mitchell 2010) also looked at children with ALL. Thrombosis risk stratification was done using a newly developed thrombosis risk stratification score. Among the elements included in the new scoring system, CVC presence (that is Broviac/Port-a-cath) was included. Four hundred and fifty-six patients were available for scoring and 339 for prospective validation of the score. Subsequently, 8/19 children scoring as high thrombotic risk received LMWH primary prophylaxis prior to CVC placement; LMWH was instituted based on physicians’ preferences. This practice led to a significant increased thrombosis-free survival in patients on LMWH (P = 0.02, log rank test). Therefore, both studies suggested a beneficial preventive antithrombotic effect in children with ALL and CVC placement, even in association with other thrombotic risk factors. Additionally, the study by Vegting (Vegting 2012) was a single centre observational study of children requiring total parenteral nutrition (TPN) administered through a CVC. In this study, patients on TPN receiving either LMWH (for example, nadroparin in a single dose of 80 IU/kg targeting an anti-Xa between 0.1 and 0.3) or an oral vitamin K antagonist (VKA) (acenocumarol, targeting an international normalised ratio (INR) between 2.0 and 3.0) were compared to patients from the same centre in whom anticoagulation prophylaxis was not utilised. The CVC-related outcomes of this cohort were CVC-related thrombosis, infection and obstruction. In sum, patients receiving thromboprophylaxis (n = 18: 16 LMWH, 2 VKA) had a lower rate of thrombosis (6%) in comparison to the children not receiving prophylaxis (n = 14,


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33%; P = 0.034). Similarly, cumulative thrombosis-free survival in the thromboprophylaxis and the non-prophylaxis groups was 93% and 48%, respectively (P = 0.04). Moreover, per 1000 TPN days, the prophylaxis and non-prophylaxis groups had 0.1 and 2.6 CVC occlusions (P = 0.04) and 2.1 and 4.6 infections (P = 0.06), respectively, with a three-year infection-free survival of 46% and 19%, respectively (P = 0.03). No bleeding occurred in either group and the study authors concluded that anticoagulation prophylaxis significantly decreased CVC-related complications in children receiving long-term TPN.

Risk of bias in included studies The risk of bias of the included study (Massicotte 2003) is shown in Figure 2 and is explained in detail in Characteristics of included studies.

Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.


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Allocation Participants were randomised using a computer-derived protocol. Allocation concealment was judged to be at unclear risk of bias as it was not specifically addressed and the study author has not provided this information.

Other potential sources of bias The study was stopped early due to the low enrolment rate (not due to data-driven reasons) and was underpowered.

Effects of interventions Blinding This is an open-label study and therefore at high risk of performance bias. However, this situation was ameliorated by the placement of an independent and blinded outcome adjudication process.

See: Summary of findings for the main comparison Low molecular weight heparin for prevention of central venous catheter (CVC)-related thrombosis in children

Primary outcome Incomplete outcome data For 28 participants (15%) no data were available regarding the efficacy outcome (venogram proven VTE). More specifically, for 23 participants (12 in the intervention arm and 11 in the control arm) the required venogram was not obtained. For the remaining five participants (two in the intervention arm and three in the control arm) the venogram results were inconclusive and hence were not included in the analysis. Selective reporting The study protocol was not available, but the published report included all expected outcomes.

CVC-related thrombosis

No statistically significant difference was evident in the incidence of CVC-related thrombosis (symptomatic and asymptomatic events) between patients in the LMWH (reviparin) arm and the control arm (standard care treatment as described above) (RR for symptomatic thrombosis 1.03, 95% CI 0.21 to 4.93; RR for asymptomatic thrombosis 1.17, 95% CI 0.45 to 3.08) (Analysis 1.1; Figure 3; Analysis 1.2; Figure 4). However, the study was not powered to detect the efficacy of LMWH prophylaxis to prevent CVC-related thrombosis in children given that its low accrual rate led to early closure of the study.

Figure 3. Forest plot of comparison: 1 Thrombosis, outcome: 1.1 Symptomatic thrombosis.

Figure 4. Forest plot of comparison: 1 Thrombosis, outcome: 1.2 Asymptomatic thrombosis.


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Secondary outcomes Only data related to the side effects of LMWH (bleeding events) and mortality were reported in the included study. No further information was available regarding the remaining pre-specified secondary outcomes.

Side effects of LMWH

With regard to bleeding events, only one patient in the standard care group suffered a major bleeding event, while minor bleeding was found in 53.3% of patients in the reviparin arm and in 44.7% of patients in the standard care arm (major bleeding RR 0.34, 95% CI 0.01 to 8.26; minor bleeding RR 1.20, 95% CI 0.91 to 1.58) (Analysis 2.1; Figure 5; Analysis 2.2; Figure 6). Figure 5. Forest plot of comparison: 2 Bleeding events, outcome: 2.1 Major bleeding.

Figure 6. Forest plot of comparison: 2 Bleeding events, outcome: 2.2 Minor bleeding.

Mortality during period of therapy

Overall, there were two deaths within the study and neither were the result of VTE, occurring in the standard care arm. Because the causes of death were not related to thrombosis, this comparison was not considered for further analysis.

DISCUSSION Summary of main results The single study included in this review (Massicotte 2003) reported the incidence of thrombosis in 92 children receiving the


12

LMWH named reviparin and 94 children receiving standard care. This trial found no clear evidence of a difference in the incidence of symptomatic and asymptomatic thrombotic events or major and minor bleeding events between the two study arms. Other predefined outcomes of this review were not reported in the included trial. The included trial was underpowered.

Overall completeness and applicability of evidence The single trial that met the inclusion criteria (Massicotte 2003) had a complete report of the primary outcome of this review, CVCrelated thrombosis. The study author was contacted to provide additional information on the secondary outcomes intended by this review, including line patency, CVC-related sepsis (as per the criteria defined above), osteopenia and heparin-induced thrombocytopenia (HIT). With regards to the applicability (that is generalisability) of their findings, the most common underlying conditions requiring CVC placement were represented allowing generalisability of the results to paediatric patients admitted to tertiary care hospitals.

Quality of the evidence The included trial has an adequate methodological design ( Massicotte 2003) and thorough report, including the study limitations and deviations from the protocol. However, it did not adequately describe the method utilised for allocation concealment. Of note, this was an open-label study, which in theory may increase the estimate of intervention effects. Nonetheless, a committee for outcome adjudication was in place, decreasing the chances of biases in this respect. In the analysis section of Massicotte 2003, an intention-to-treat approach was followed for the primary outcome (that is thrombotic events). However, two patients randomised to receive the intervention and who subsequently did not receive the study drug were not included in the final analysis of bleeding events. Lastly, the study was closed prematurely due to low accrual, yielding an underpowered study. The low number of participants recruited and the wide confidence intervals for the effect estimates prompted us to downgrade the quality of the evidence from high to low (Summary of findings for the main comparison).

Potential biases in the review process We searched for published and unpublished abstracts and manuscripts in a comprehensive literature review supervised by an experience librarian and conducted by the authors. This search was not limited to a particular language. Study authors were contacted to fill in data that was missing in the original publications or abstracts. However, a minor limitation of this review is the fact

that it was not possible to collect all relevant information from the included trial, particularly efficacy data regarding CVC patency and safety data regarding osteopenia, coagulopathy and allergic reactions secondary to LMWH use, as these outcomes were not included in the study.

Agreements and disagreements with other studies or reviews Several retrospective and prospective studies have reported the incidence of thrombosis in children with CVCs (Andrew 1995; Monagle 2012). More recent studies continue to show the rise of thrombotic events in children, particularly due to the higher incidence of CVC-related thrombosis (Raffini 2009). In light of the potential morbidity associated with thrombosis-related complications (Monagle 2012), prophylaxis with LMWH has increasingly been considered (Raffini 2011) as thrombosis has become a very clinically relevant complication. Nevertheless, in the absence of more convincing prospective paediatric studies, recent guidelines do not support primary prophylaxis for children with CVCs (Chalmers 2011; Monagle 2012). The study conducted by Massicotte et al (Massicotte 2003) is the only study comparing LMWH with standard care randomly assigned to children from all the main categories of paediatric conditions in which CVC placement is now routine. Even though this study was underpowered, it suggested no difference in the incidence of CVC-related thrombosis despite LMWH prophylaxis. Three other studies of different design suggested differently (Harlev 2010; Mitchell 2010; Vegting 2012). Because the study population included in the study by Vegting 2012, that is children receiving TPN, is different from the populations of the other two studies, that is children with ALL treated by the same chemotherapy protocol (Harlev 2010; Mitchell 2010), we should compare the results from the Massicotte 2003 randomised controlled trial with each of the two study groups separately (Vegting 2012 and Harlev 2010; Mitchell 2010). Harlev 2010 and Mitchell 2010 were not randomised, increasing their chances for biases and study limitations. Similarly, the use of LMWH within their population was not only aimed at preventing CVC-related thrombosis but all types of thrombosis in children with ALL considered at higher risk, of which CVC was included. Notwithstanding, both studies suggested that for this specific paediatric group of ALL patients LMWH may be warranted for the prevention of thrombotic events, including in patients with CVCs. This information is likely to be very relevant for all paediatric populations with a higher risk of thrombosis development, given that CVCs are potentially the most relevant thrombosis risk factor in place (O’Brien 2011). In regards to their discrepant findings, the proportions of the two main underlying conditions in Massicotte 2003 were congenital heart disease (22.5%) and cancer (50%). The population of the two excluded cohort studies (Harlev 2010; Mitchell 2010)


13

was comprised only of children with ALL (cancer), a more homogeneous and maybe more prothrombotic population. Because thrombosis in children is multifactorial, it is plausible that added risk factors are required to trigger such complications. Therefore, populations carrying different risks due to their different nature could vary in their contributions in terms of thrombosis risks, providing a reasonable explanation for the differences noted herein. In fact, even within the same underlying condition, as shown by the study of Mitchell et al (Mitchell 2010), thrombosis risk stratification is likely to be required for the institution of LMWHbased or any other type of anticoagulant-based prophylaxis. Secondly, since the anticoagulant effect of LMWH may depend on normal-for-age circulating levels of antithrombin (AT), a natural anticoagulant that potentiates the action of heparin and LMWH, underlying conditions resulting in different degrees of AT consumption may affect the efficacy of LMWH prophylaxis differently, as suggested by a recent study comparing LMWH alone versus LMWH in addition to AT replacement in children with ALL (Melster 2008). Thirdly, the study of Massicotte et al (Massicotte 2003) relied on the combination of Doppler ultrasound (US) and a venogram, the gold standard modality for detection of upper and lower extremity thrombosis in children. This combination is particularly accurate for upper extremity events, which comprise almost 50% of events in children given the relation to CVC placement. The two other studies would have relied on Doppler US alone to diagnose thrombi. Therefore, we could hypothesise that the use of different imaging modalities may have contributed to the disagreements among the studies. Conversely, the study by Vegting et al (Vegting 2012) was a single centre observational study that combined data obtained retrospectively and prospectively. In this study, CVC-related outcomes encountered in children receiving TPN, with (n = 18) or without (n = 27) anticoagulation prophylaxis, were obtained. Of note, approximately 75% of patients included in the prophylaxis arm were previously included in the non-prophylaxis group as the clinic’s anticoagulation policy for children receiving TPN was changed for all patients. Their findings suggested a potential benefit for the use of LMWH in children receiving TPN via a CVC as CVCrelated infections, occlusion and thrombosis were less prevalent in patients receiving thromboprophylaxis in comparison to the patients on TPN without thromboprophylaxis. Once more, the discrepant conclusions between the study by Vegting et al (Vegting 2012) and by Massicotte et al (Massicotte 2003) may be explained by the multifactorial nature of thrombosis in children. More specifically, the population included in the former study was a much more homogeneous one (100% TPN-dependent) whereas in the latter study the percentage of TPN-dependent patients was not specified but was likely to be equal to or lower than 16% to 21%. Furthermore, children with TPN administered by central venous catheters are recognizably amongst the highest risk groups for CVC-related thrombosis development

(Andrew 1995). In such patients, the nature of the infusate, leading to local vessel wall inflammation, in addition to protein precipitation within the catheter lumen contribute to a likely high rate of CVC-related complications. Depending on the time of CVC insertion, thrombosis risk factors will have greater or lesser importance. Given the study design of the first study (Vegting 2012), the interpretation of the results has significant limitations as 13/18 patients from the thromboprophylaxis arm had already had their CVC inserted and been exposed to TPN for a considerable time before they entered “the intervention study arm”, likely leading to exposure to risk factors in an unbalanced and different manner. Similarly, a younger age also predisposes children to CVC-related thrombotic complications and hence the same study limitation applies. Therefore, while the study findings suggest that LMWH is safe and beneficial in terms of CVC-related outcome prevention for children receiving TPN, further prospective studies with a more appropriate design are required. Because of the particular characteristics of TPN-related thrombotic events, mentioned herein, the generalisibility of such findings to children with a CVC and who are not receiving TPN requires caution, likely contributing to the discrepant results as shown by the randomised controlled trial (Massicotte 2003).

AUTHORS’ CONCLUSIONS Implications for practice A single study reported imprecise effects for the risk of CVC-related thrombosis in children on a CVC anticoagulant prophylaxis regimen. The quality of the evidence was low due to the fact that the included study was clearly underpowered, hampering any conclusions in regards to the efficacy of LMWH prophylaxis to prevent CVC-related thrombi in children.

Implications for research Since the reported incidence of symptomatic CVC-related thrombosis in children is approximately 10%, a trial evaluating the superiority of LMWH prophylaxis in comparison to standard care will require at least 856 patients in total (that is 428 patients per arm in a one to one allocation) to achieve 80% power to detect a 50% relative risk reduction of symptomatic thrombosis, which can be considered clinically meaningful. The two-sided significance level (1-alpha) was set at 95. Open-Epi software was utilised for the sample size calculation. Therefore, other multicentre randomised trials are required to answer this question, a task not completed by the reported manuscript (Massicotte 2003). However, many lessons can be learned from this report (that is the relatively large number of exclusions, responsible for 31% of problems with enrolment). Given the increasing placement of CVCs in modern paediatric care, and


14

that paediatric hospital accreditation may be conditioned to the development of age and scenario-specific prophylaxis protocol development in the near future, there will be a continued need to conduct trials evaluating this problem. Trials should aim to evaluate the role of patient age, risk factors, and of additional prophylactic modalities such as new oral anticoagulant agents, warfarin and CVC flushes. Lastly, the potential cost of any prophylactic intervention should also be addressed in future studies.

ACKNOWLEDGEMENTS We acknowledge Ms Elizabeth Uleryk for her invaluable expertise in developing the authors’ search strategy.

REFERENCES

References to studies included in this review Massicotte 2003 {published data only} Massicotte P, Julian JA, Gent M, Shields K, Marzinotto V, Szechtman B, et al.PROTEKT Study Group. An openlabel randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial. Thrombosis Research 2003;109(2-3):101–8.

References to studies excluded from this review Abdelkefi 2004 {published data only} Abdelkefi A, Ben Othman T, Kammoun L, Chelli M, Romdhane NB, Kriaa A, et al.Prevention of central venous line-related thrombosis by continuous infusion of lowdose unfractionated heparin, in patients with haematooncological disease. A randomized controlled trial. Thrombosis and Haemostasis 2004;92(3):654–61. Cavo 2010 {published data only} Cavo M, Wang W, O’Brien SH. Use of low molecular weight heparin for thromboprophylaxis in a pediatric inpatient population: reasons for use and incidence of bleeding complications. Thrombosis Research 2010;125(4): 370–2. De Cicco 2009 {published data only} De Cicco M, Matovic M, Balestreri L, Steffan A, Pacenzia R, Malafronte M, et al.Early and short-term acenocumarine or dalteparin for the prevention of central venous catheterrelated thrombosis in cancer patients: a randomized controlled study based on venographies. Annals of Oncology 2009;20(12):1936–42. Harlev 2010 {published data only} Harlev D, Zaidman I, Sarig G, Ben Arush MW, Brenner B, Elhasid R. Prophylactic therapy with enoxaparin in children with acute lymphoblastic leukemia and inherited

thrombophilia during L-asparaginase treatment. Thrombosis Research 2010;126(2):93–7. Harney 2010 {published data only} Harney KM, McCabe M, Branowicki P, Kalish LA, Neufeld EJ. Observational cohort study of pediatric inpatients with central venous catheters at “intermediate risk” of thrombosis and eligible for anticoagulant prophylaxis. Journal of Pediatric Oncology Nursing 2010;27(6):325–9. Karthaus 2006 {published data only} Karthaus M, Kretzschmar A, Kroning H, Biakhov M, Irwin D, Marschner N, et al.Dalteparin for prevention of catheterrelated complications in cancer patients with central venous catheters: final results of a double-blind, placebo-controlled phase III trial. Annals of Oncology 2006;17(2):289–96. Mismetti 2003 {published data only} Mismetti P, Mille D, Laporte S, Charlet V, BuchmüllerCordier A, Jacquin JP, et al.CIP Study Group. Low molecular weight heparin (nadroparin) and very low doses of warfarin in the prevention of upper extremity thrombosis in cancer patients with indwelling long-term central venous catheters: a pilot randomized trial. Haematologica 2003;88 (1):67–73. Mitchell 2010 {published data only} Mitchell L, Lambers M, Flege S, Kenet G, Li-Thiao-Te V, Holzhauer 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. Monreal 1996 {published data only} Monreal M, Alastrue A, Rull M, Mira X, Muxart J, Rosell R, et al.Upper extremity deep venous thrombosis in cancer patients with venous access devices--prophylaxis with a low molecular weight heparin (Fragmin). Thrombosis and Haemostasis 1996;75(2):251–3.


15

Niers 2007 {published data only} Niers TM, Di Nisio M, Klerk CP, Baarslag HJ, Buller HR, Biemond BJ. Prevention of catheter-related venous thrombosis with nadroparin in patients receiving chemotherapy for hematologic malignancies: a randomized, placebo-controlled study. Journal of Thrombosis and Haemostasis 2007;5(9):1878–82. Raffini 2011 {published data only} Raffini L, Trimarchi T, Beliveau J, Davis D. Thromboprophylaxis in a pediatric hospital: A patientsafety and quality-improvement initiative. Pediatrics 2011; 127(5):e1326–32. Sandoval 2008 {published data only} Sandoval JA, Sheehan MP, Stonerock CE, Shafique S, Rescorla FJ, Dalsing MC. Incidence, risk factors and treatment patterns for deep venous thrombosis in hospitalized children: an increasing population at risk. Journal of Vascular Surgery 2008;47(4):837–43.

access devices in pediatric patients with cancer: algorithms for decision making. Oncology Nursing Forum 1990;17(5): 677–81. Bona 2003 Bona RD. Central line thrombosis in patients with cancer. Current Opinion in Pulmonary Medicine 2003;9(5):362–6. Broviac 1973 Broviac JW, Cole JJ, Scribner BH. A silicone rubber atrial catheter for prolonged alimentation. Surgery, Gynecology and Obstetrics 1973;136(4):602–6. Carde 1989 Carde P, Cosset-Delaigue MF, Laplanche A, Chareau I. Classical external indwelling central venous catheter versus totally implanted venous access systems for chemotherapy administration: a randomized trial in 100 patients with solid tumors. European Journal of Cancer and Clinical Oncology 1989;25(6):939–44.

Trame 2010 {published data only} Trame MN, Mitchell L, Krümpel A, Male C, Hempel G, Nowak-Göttl U. Population pharmacokinetics of enoxaparin in infants, children and adolescents during secondary thromboembolic prophylaxis: a cohort study. Journal of Thrombosis and Haemostasis 2010;8(9):1950–8.

Chalmers 2011 Chalmers E, Ganesen V, Liesner R, Maroo S, Nokes T, Saunders D, et al.British Committee for Standards in Haematology. Guidelines on the investigation, management and prevention of venous thrombosis in children. British Journal of Haematology 2011;154(2):196–207.

van Ommen 2010 {published data only} van Ommen CH, Tabbers MM. Catheter-related thrombosis in children with intestinal failure and longterm parenteral nutrition: how to treat and to prevent?. Thrombosis Research 2010;126(6):465–70.

Finkelstein 2004 Finkelstein Y, Yaniv I, Berant M, Zilber R, Garty BZ, Epstein O, et al.Central venous line thrombosis in children and young adults with thalassemia major. Pediatric Hematology and Oncology 2004;21(5):375–81.

Vegting 2012 {published data only} Vegting IL, Tabbers MM, Benninga MA, WIlde JC, Serlie MJ, Tas TA, et al.Prophylactic anticoagulation decreases catheter-related thrombosis and occlusion in children with home parenteral nutrition. Journal of Parenteral and Enteral Nutrition 2012;36(4):456–62.

Fratino 2005 Fratino G, Molinari AC, Parodi S, Longo S, Saracco P, Castagnola E, et al.Central venous catheter-related complications in children with oncological/hematological diseases: an observational study of 418 devices. Annals of Oncology 2005;16(4):648–54.

Verso 2005 {published data only} Verso M, Agnelli G, Bertoglio S, Di Somma FC, Paoletti F, Ageno W, et al.Enoxaparin for prevention of thromboembolism associated with central vein catheter: a double-blind, placebo-controlled, randomized study in cancer patients. Journal of Clinical Oncology 2005;23(18): 4057–62.

Guyatt 2008 Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schunemann HJ, et al.What is “Quality of evidence” and why is it important to clinicians?. BMJ 2008;336(7651): 995–8.

Additional references Andrew 1995 Andrew M, Marzinotto V, Pencharz P, Zlotkin S, Burrows P, Ingram J, et al.A cross-sectional study of catheter-related thrombosis in children receiving total parenteral nutrition at home. Journal of Pediatrics 1995;126(3):358–63. Anton 2001 Anton N, Massicotte MP. Venous thromboembolism in pediatrics. Seminars in Vascular Medicine 2001;1(1): 111–22. Bagnall-Reeb 1990 Bagnall-Reeb HA, Ruccione K. Management of cutaneous reactions and mechanical complications of central venous

Hickman 1979 Hickman RO, Buckner CD, Clift RA, Sanders JE, Stewart P, Thomas ED. A modified atrial catheter for access to the venous system in marrow transplant recipients. Surgery, Gynecology and Obstetrics 1979;148(6):871–5. Higgins 2008 Higgins JPT, Altman DG (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Chichester: John Wiley & Sons, Ltd, 2008. Klerk 2003 Klerk CP, Smorenburg SM, Büller HR. Thrombosis prophylaxis in patient populations with a central venous catheter: a systematic review. Archives of Internal Medicine 2003;163(16):1913–21.


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Krafte-Jacobs 1995 Krafte-Jacobs B, Sivit CJ, Mejia R, Pollack MM. Catheterrelated thrombosis in critically ill children: comparison of catheters with and without heparin bonding. Journal of Pediatrics 1995;126(1):50–4. Male 2003 Male C, Chait P, Andrew M, Hanna K, Julian J, Mitchell L, PARKAA Investigators. Central venous line-related thrombosis in children: association with central venous line location and insertion technique. Blood 2003;101(11): 4237–8. Mclean 2005 McLean TW, Fisher CJ, Snively BM, Chauvenet AR. Central venous lines in children with lesser risk acute lymphoblastic leukemia: optimal type and timing of placement. Journal of Clinical Oncology 2005;23(13): 3024–9. Melster 2008 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. Pediatric Blood and Cancer 2008;50(2):298–303. Monagle 2012 Monagle P, Chan AK, Goldenberg NA, Ichord RN, Journeycake JM, Nowak-Göttl U, et al.Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th Edition: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e737S–801S. Nowak-Göttl 1999 Nowak-Göttl U, Wermes C, Junker R, Koch HG, Schobess R, Fleischhack G, et al.Prospective evaluation of the thrombotic risk in children with acute lymphoblastic

leukemia carrying the MTHFR TT 677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors. Blood 1999;93(5):1595–9. O’Brien 2011 O’Brien SH, Candrilli SD. In the absence of a central venous catheter, risk of venous thromboembolism is low in critically injured children, adolescents, and young adults: evidence from the National Trauma Data Bank. Pediatric Critical Care Medicine 2011;12(3):251–6. Raffini 2009 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(4):1001–8. Randolph 1998 Randolph AG, Cook DJ, Gonzales CA, Andrew M. Benefit of heparin in central venous and pulmonary artery catheters: a meta-analysis of randomized controlled trials. Chest 1998; 113(1):165–71. Shah 2008 Shah PS, Shah VS. Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: 10.1002/14651858.CD002772.pub3] Steele 2001 Steele R, Irvin CB. Central line mechanical complication rate in emergency medicine patients. Academic Emergency Medicine 2001;8(2):204–7. Vidler 1999 Vidler V, Richards M, Vora A. Central venous catheterassociated thrombosis in severe haemophilia. British Journal of Haematology 1999;104(3):461–4. ∗ Indicates the major publication for the study


17

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Massicotte 2003 Methods

Open-label randomised controlled trial of low molecular weight heparin for prevention of CVC-related thrombosis in children

Participants

Newborns > 36 weeks gestational age to children < 18 years; if age < 36 weeks, then weight > 5 kg at randomisation CVC placed for the first time The neonates, infants and children with a newly placed CVC were subsequently screened by examination or by imaging at CVC removal (i.e. day + 30) Age: LMWH (reviparin) prophylaxis mean age: 6.1 yr (standard deviation (SD) 5.2 yr) ; standard of care mean age: 6.4 yr (SD 5.0 yr)

Interventions

Reviparin: 30 IU/kg if < 3 months; 50 IU/kg if ≥ 3 months (dose as per previous ageappropriate pharmacokinetic findings) Control/comparison: Unfractionated heparin flushes or very low doses infusion of unfractionated heparin (< 3 IU/kg/hour)

Outcomes

Primary: CVC-related venous thromboembolism (VTE) detected by an exit venogram at day + 30 (+ 14 d) or at the time of CVC removal (+ 14 days) if < 30 days, a confirmed symptomatic VTE within 30 d of CVC placement, or death due to thrombosis during the study period

Notes

Underpowered, closed prematurely due to low enrolment rate

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Quote: “They were randomly assigned by a computer-derived protocol to receive...”

Allocation concealment (selection bias)

Not enough information available

Unclear risk

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

Quote: “The PROTEKT trial was an openlabel randomised controlled trial”

Blinding of outcome assessment (detection Low risk bias) All outcomes

Quote: “An independent and blinded Central Adjudication Committee assessed all efficacy and safety outcomes.”

Incomplete outcome data (attrition bias) All outcomes

Missing outcome data balanced between study arms (for thrombotic events: 14/92 for reviparin arm versus 14/94 for standard

Low risk


18

Massicotte 2003

(Continued)

of care arm; for bleeding events: 2/92 reviparin arm versus 0/94 for standard of care arm), with similar reasons for missing outcome data (quote: “For 23 patients (12 receiving reviparin-sodium and 11 standard care), the mandatory venogram was not done, usually because of an inability of the patient to be transported to the radiology department. For the other five patients (two reviparin-sodium, three standard care), the venograms were indeterminate.” Selective reporting (reporting bias)

Low risk

The study protocol is not available, but the published report includes all expected outcomes

Other bias

Low risk

The study was stopped early due to low enrolment rate (not due to data-driven reasons)

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Abdelkefi 2004

Prospective randomised trial in adults with haemato-oncological conditions receiving heparin infusion for thrombosis prevention

Cavo 2010

Retrospective cohort study of patients receiving low molecular weight heparin prophylaxis identified as per ICD-9-CM codes

De Cicco 2009

Prospective randomised trial comparing short-term prophylaxis with either dalteparin or low dose acenocumarine in adults with cancer for prevention of venography-proven catheter-related thrombosis

Harlev 2010

Retrospective cohort study of paediatric patients with acute lymphoblastic leukaemia, either receiving or not LMWH prophylaxis according to the practice of different periods of time

Harney 2010

Retrospective cohort study in paediatric patients with CVC admitted to intensive care unit

Karthaus 2006

Prospective, double-blinded, placebo-controlled study in adult cancer patients receiving dalteparin to prevent central venous catheter-related thrombosis

Mismetti 2003

Prospective, open-label, randomised trial comparing the LMWH nadroparin to low dose warfarin in adult cancer patients with central venous catheters

Mitchell 2010

Prospective paediatric cohort study for validation of a clinical predictive model for thrombosis development in children with acute lymphoblastic leukaemia


19

(Continued)

Monreal 1996

Prospective open-label, randomised trial enrolling only adults with cancer and central catheter devices receiving dalteparin as prophylaxis

Niers 2007

Prospective, randomised, double-blinded, placebo-controlled study in adult patients with hematologic cancer receiving nadroparin for prevention of catheter-related thrombosis

Raffini 2011

Prospective study to assess compliance to thromboprophylaxis guidelines in children

Sandoval 2008

Retrospective cohort study on risk factors for thrombosis in hospitalised children

Trame 2010

Prospective study for the evaluation of pharmacokinetic of enoxaparin in children

van Ommen 2010

Retrospective cohort study for prophylaxis candidates among children on long-term parenteral nutrition

Vegting 2012

Observational study for anticoagulation prophylaxis of children receiving total parenteral nutrition, including a retrospective and a partly prospective source of data

Verso 2005

Randomised, double-blinded, placebo-controlled study in adult cancer patients receiving enoxaparin for central venous catheter-related thrombosis prevention


20

DATA AND ANALYSES

Comparison 1. LMWH versus standard care for CVC: thrombosis

Outcome or subgroup title

No. of studies

1 Symptomatic thrombosis 2 Asymptomatic thrombosis

1 1

No. of participants

Statistical method

Effect size

Risk Ratio (IV, Fixed, 95% CI) Risk Ratio (IV, Fixed, 95% CI)

Totals not selected Totals not selected

Comparison 2. LMWH versus standard care for CVC: bleeding events

No. of studies

Outcome or subgroup title 1 Major bleeding 2 Minor bleeding

No. of participants

1 1

Statistical method

Effect size

Risk Ratio (IV, Fixed, 95% CI) Risk Ratio (IV, Fixed, 95% CI)

Totals not selected Totals not selected

Analysis 1.1. Comparison 1 LMWH versus standard care for CVC: thrombosis, Outcome 1 Symptomatic thrombosis. Review:

Low molecular weight heparin for prevention of central venous catheterization-related thrombosis in children

Comparison: 1 LMWH versus standard care for CVC: thrombosis Outcome: 1 Symptomatic thrombosis

Study or subgroup

Massicotte 2003

LMWH

Control

Risk Ratio

Risk Ratio

n/N

n/N

IV,Fixed,95% CI

IV,Fixed,95% CI

3/78

3/80

1.03 [ 0.21, 4.93 ]

0.2

0.5

Favours LMWH

1

2

5

Favours control


21

Analysis 1.2. Comparison 1 LMWH versus standard care for CVC: thrombosis, Outcome 2 Asymptomatic thrombosis. Review:


Comparison: 1 LMWH versus standard care for CVC: thrombosis Outcome: 2 Asymptomatic thrombosis

Study or subgroup

Massicotte 2003

LMWH

Control

Risk Ratio

Risk Ratio

n/N

n/N

IV,Fixed,95% CI

IV,Fixed,95% CI

8/78

7/80

1.17 [ 0.45, 3.08 ]

0.01

0.1

1

Favours LMWH

10

100

Favours control

Analysis 2.1. Comparison 2 LMWH versus standard care for CVC: bleeding events, Outcome 1 Major bleeding. Review:


Comparison: 2 LMWH versus standard care for CVC: bleeding events Outcome: 1 Major bleeding

Study or subgroup

Massicotte 2003

LMWH

Control

Risk Ratio

Risk Ratio

n/N

n/N

IV,Fixed,95% CI

IV,Fixed,95% CI

0/78

1/80

0.34 [ 0.01, 8.26 ]

0.001 0.01 0.1 Favours LMWH

1

10 100 1000 Favours control


22

Analysis 2.2. Comparison 2 LMWH versus standard care for CVC: bleeding events, Outcome 2 Minor bleeding. Review:


Comparison: 2 LMWH versus standard care for CVC: bleeding events Outcome: 2 Minor bleeding

Study or subgroup

Massicotte 2003

LMWH

Control

Risk Ratio

Risk Ratio

n/N

n/N

IV,Fixed,95% CI

IV,Fixed,95% CI

48/78

41/80

1.20 [ 0.91, 1.58 ]

0.05

0.2

Favours LMWH

1

5

20

Favours control

APPENDICES Appendix 1. CENTRAL search strategy

1

MeSH descriptor: [Catheterization, Central Venous] explode 711 all trees

#2

MeSH descriptor: [Catheters] explode all trees

966

#3

broviac

26

#4

port near/3 cath

42

#5

portacath

8

#6

hickman

179

#7

catheter*

12832

#8

TCVC or PICC or CVC or CVAD

322

#9

venous near/3 (line or device)

289

#10

cannula*

1653


23

(Continued)

#11

#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10

14107

#12

MeSH descriptor: [Thrombosis] explode all trees

4753

#13

thrombo* or clot*

25385

#14

#12 or #13

25594

#15

#11 and #14

1637

#16

MeSH descriptor: [Heparin, Low-Molecular-Weight] explode 1632 all trees

#17

*heparin* or LMWH or nadroparin* or fraxiparin* or enoxa- 8499 parin or Clexane or klexane or lovenox or dalteparin or Fragmin or ardeparin or normiflo or tinzaparin or logiparin or Innohep or certoparin or sandoparin or reviparin or clivarin* or danaproid or danaparoid or bemiparin or bioparin or Alphaparin or Troparin

#18

antixarin or ardeparin* or bemiparin* or Zibor or cy 222 or 196 embolex or monoembolex or Mono-embolex or parnaparin* or “rd 11885” or tedelparin or Kabi-2165 or Kabi 2165

#19

emt-966 or emt-967 or pk-10169 or pk10169

#20

cy-216 or cy216 or seleparin* or tedegliparin or seleparin* or 85 tedegliparin* or tedelparin or Boxol or Liquemine

#21

fr-860

14

#22

wy90493 or wy-90493

10

#23

kb-101 or kb101 or lomoparan or orgaran

65

#24

parnaparin or fluxum or lohepa or lowhepa or “op 2123” or 52 parvoparin

#25

AVE5026 or M118 or RO-14

#26

#16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or # 8566 24 or #25

#27

#15 and #26 in Trials

20

44

335


24

Appendix 2. Authors’ MEDLINE search strategy

Set

History

Results

Comments

1

catheters/ or catheters, indwelling/ or 108618 catheterization/ or catheterization, central venous/ or heart catheterization/ or catheterization, swan-ganz/

Catheter Terms

2

exp Heparin, Low-Molecular-Weight/

9890

Heparin Terms

3

exp Thrombosis/ or prophyla*.mp.

254495

Outcome Terms

4

1 and 2 and 3

125

FINAL Results

Appendix 3. Authors’ EMBASE search strategy

Set

History

Results

1

catheter/ or “catheters and tubes”/ or exp 98873 central venous catheter/ or indwelling catheter/ or intravenous catheter/ or subclavian vein catheter/ or umbilical artery catheter/ or Swan Ganz catheter/ or blood vessel catheterization/ or catheterization/ or exp artery catheterization/ or exp vein catheterization/

Catheter Terms

2

exp low molecular weight heparin/

Heparin Terms

3

thromboembolism/ or exp embolism/ or 484432 exp thrombosis/ or exp venous thromboembolism/ or prophylaxis/ or embolism prevention/ or thrombosis prevention/ or prophyla*.mp

Outcome Terms

4

1 and 2 and 3

FINAL Results

38879

979

Comments


25

FEEDBACK Anticoagulant feedback, 14 February 2011

Summary Feedback received on this protocol, and other reviews and protocols on anticoagulants, is available on the Cochrane Editorial Unit Website at http://www.editorial-unit.cochrane.org/anticoagulants-feedback.

HISTORY Protocol first published: Issue 2, 2006 Review first published: Issue 3, 2014

Date

Event

Description

1 May 2013

Amended

Link to anticoagulant feedback added

30 October 2008

Amended

Converted to new review format.

CONTRIBUTIONS OF AUTHORS LR Brandão selected trials, assessed trial quality, extracted data and wrote the final review. N Shah selected trials, assessed trial quality, extracted data, and wrote and edited the final review. PS Shah assessed trial quality, collaborated using his methodological expertise and edited the final review.

DECLARATIONS OF INTEREST None known

SOURCES OF SUPPORT Internal sources • The Department of Pediatrics, Mount Sinai Hospital, Toronto, Canada. • Department of Hematology and Oncology, Haemostasis and Thrombosis Program, The Hospital For Sick Children, Toronto, Canada.


26

External sources • Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK. The PVD Group editorial base is supported by the Chief Scientist Office

DIFFERENCES BETWEEN PROTOCOL AND REVIEW The planned assessments of the methodological quality of the included studies has been replaced by the risk of bias tool from The Cochrane Collaboration (Higgins 2008).

INDEX TERMS Medical Subject Headings (MeSH) Anticoagulants [∗ therapeutic use]; Catheterization, Central Venous [∗ adverse effects]; Heparin, Low-Molecular-Weight [∗ therapeutic use]; Randomized Controlled Trials as Topic; Thrombosis [etiology; ∗ prevention & control]

MeSH check words Adolescent; Child; Child, Preschool; Humans; Infant


27

Low molecular weight heparin in prevention of perioperative thrombosis.

Therapeutic application of subcutaneous low-molecular-weight heparin in acute venous thrombosis.

Randomized controlled study of heparin and low molecular weight heparin for prevention of deep-vein thrombosis in medical patients.

Treatment of deep venous thrombosis by fixed doses of a low-molecular-weight heparin (CY216).

Prevention of deep vein thrombosis in patients with hip fractures: low molecular weight heparin versus dextran.

Low molecular weight heparin in management and prevention of portal vein thrombosis.

The efficacy and safety of low-molecular-weight heparin and unfractionated heparin in the treatment of cerebral venous sinus thrombosis.

Low molecular weight heparin versus unfractionated heparin in the management of cerebral venous thrombosis: A systematic review and meta-analysis.

Dose adjusted heparin treatment of deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin.

Deep venous thrombosis and left ventricular thrombosis prophylaxis by low molecular weight heparin in acute myocardial infarction.

Prevention of deep vein thrombosis after hip replacement: randomised comparison between unfractionated heparin and low molecular weight heparin.

Low-molecular-weight heparin.

Low molecular weight heparin.

Low molecular weight heparin.

Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis.

The Efficacy of Low Molecular Weight Heparin for the Prevention of Venous Thromboembolism after Hip Fracture Surgery in Korean Patients.

[Low-molecular weight heparin. Chemical and pharmacologic characteristics of a new substance group for postoperative thrombosis prevention].

Rationale for development of low-molecular-weight heparins and their clinical potential in the prevention of postoperative venous thrombosis.

[Postoperative thrombosis prevention using low-dose heparin].

Rivaroxaban vs. low molecular weight heparin for the prevention of venous thromboembolism after hip or knee arthroplasty: a cohort study.

Comparison of low molecular weight heparin vs. unfractionated heparin in gynecological surgery. II: Reduced dose of low molecular weight heparin.

Is there any future for low-molecular-weight heparin in the prevention of pregnancy loss?

Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis.

Low molecular weight heparin in portal vein thrombosis of cirrhotic patients: only therapeutic purposes?