Journal of Thrombosis and Haemostasis, 12: 1096–1109

DOI: 10.1111/jth.12598

ORIGINAL ARTICLE

Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis E . V I D A L , * A . S H A R A T H K U M A R , † J . G L O V E R ‡ and E . V . S . F A U S T I N O § *Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA; †Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL; ‡Cushing/Whitney Medical Library, Yale School of Medicine; and §Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA

To cite this article: Vidal E, Sharathkumar A, Glover J, Faustino EVS. Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis. J Thromb Haemost 2014; 12: 1096–109.

Summary. Objectives: In preparation for a pediatric randomized controlled trial on thromboprophylaxis, we determined the frequency of catheter-related thrombosis in children. We also systematically reviewed the pediatric trials on thromboprophylaxis to evaluate its efficacy and to identify possible pitfalls in the conduct of these trials. Patients/Methods: We searched MEDLINE, EMBASE, Web of Science and the Cochrane Central Register for Controlled Trials for articles published until December 2013. We included cohort studies and trials on patients aged 0–18 years with central venous catheters who underwent active surveillance for thrombosis with radiologic imaging. We estimated the pooled frequency of thrombosis and the pooled risk ratio (RR) with thromboprophylaxis by using a random effects model. Results: From 2651 articles identified, we analyzed 37 articles with 3128 patients. The pooled frequency of thrombosis was 0.20 (95% confidence interval [CI] 0.16–0.24). In 10 trials, we did not find evidence that heparin-bonded catheters (RR 0.34; 95%CI 0.01–7.68), unfractionated heparin (RR 0.93; 95% CI 0.57–1.51), low molecular weight heparin (RR 1.13; 95% CI 0.51–2.50), warfarin (RR 0.85; 95% CI 0.34–2.17), antithrombin concentrate (RR 0.76; 95% CI 0.38–1.55) or nitroglycerin (RR 1.53; 95% CI 0.57–4.10) reduced the risk of thrombosis. Most of the trials were either not powered for thrombosis or were powered to detect large, probably unachievable, reductions in thrombosis. Missing data on thrombosis also limited these Correspondence: Elyor Vidal, Department of Structural and Cellular Biology, Tulane University School of Medicine, Box SL49, Room 3004, 1430 Tulane Avenue, New Orleans, LA 70112, USA. Tel.: +1 512 947 0846; fax: +1 504 988 1687. E-mail: [email protected] Received 1 April 2014 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 29 April 2014

trials. Conclusions: Catheter-related thrombosis is common in children. An adequately powered multicenter trial that can detect a modest, clinically significant reduction in thrombosis is critically needed. Missing outcome data should be minimized in this trial. Keywords: anticoagulants; heparin; pediatrics; prevention; prophylaxis.

Introduction Every year in the USA, deep vein thrombosis (DVT) and its complications, including pulmonary embolism, affect > 600 000 Americans, contribute to > 180 000 deaths, and cost > $27.2 billion [1]. DVT and pulmonary embolism are the most common preventable causes of death in hospitalized adults. Pharmacologic thromboprophylaxis significantly reduces the risk of unprovoked DVT in adults [2]. In hospitalized children, there is growing concern about the rising incidence of DVT [3]. Healthcare providers are pressed with an urgent need to prevent DVT in children. Because of a paucity of data on thromboprophylaxis in children, pediatric hospitals are developing local policies to prevent DVT with strategies intended for adults [4,5]. The presence of central venous catheters (CVCs) is the single most important risk factor for DVT in children [6]. At least 85% of DVTs are related to CVCs [4,7], and nearly all DVT-related deaths are associated with CVCs [6]. The frequency of CVC-related DVT in children is unclear, and ranges from 0% to 81% [8,9]. The uncertainty regarding its frequency is partly related to whether only clinically apparent DVT is analyzed. Asymptomatic DVT is significantly more common than clinically apparent DVT, and can also result in adverse outcomes, such as pulmonary embolism, embolic stroke, bloodstream infection, and loss of venous access [6]. © 2014 International Society on Thrombosis and Haemostasis

Catheter-related thrombosis in children 1097

Because CVCs remain a vital component of care, efforts need to focus on developing evidence-based strategies to prevent CVC-related DVT in children. Potentially modifiable risk factors for DVT, including the type and site of insertion of the CVC, require attention. The efficacy of thromboprophylaxis against CVC-related DVT in children is also unclear [6]. Strategies need to be evaluated in the context of emerging data regarding their efficacy. Expertly designed and conducted randomized controlled trials (RCTs) are critically needed to prevent CVC-related DVT in children. In preparation for an RCT on thromboprophylaxis, we aimed to determine the frequency of CVC-related DVT in children, including that based on type and site of insertion of the CVC. We also systematically reviewed the pediatric RCTs on thromboprophylaxis to evaluate its efficacy and to identify possible pitfalls in the conduct of these trials. Patients and methods Eligibility criteria

We included cohort studies and RCTs that recruited patients aged 0–18 years with any type of CVC. Only articles in which all patients underwent active surveillance for CVC-related DVT with radiologic imaging were included. Radiologic imaging included ultrasonography, venography, echocardiography, and magnetic resonance imaging. In studies with multiple publications, we only included the article in which the primary results of the study were reported. We excluded articles in which only heparin-bonded CVCs were used. Data sources and searches

We searched MEDLINE (OvidSP), EMBASE (OvidSP), Web of Science (Thomson Reuters) and the Cochrane Central Register for Controlled Trials (Wiley Online) for articles from inception of the database until December 2013 (Fig. 1). We also searched the Conference Proceedings Citation Index via Web of Science (Thomson Reuters) for conference abstracts. With the guidance of a medical research librarian (J.G.), two authors (E.V. and E.V.S.F.) developed and refined the search terms and performed the search. In the search strategy, we used controlled vocabulary words and synonymous free text words to capture the concepts of venous thrombosis and catheter. These clustered concepts were then linked with Boolean logic. The strategy was limited to humans and to the 0–18-year age group, but was not limited by language of publication. Data S1 provides the detailed search strategy. We identified the RCTs on thromboprophylaxis from the included studies. We also searched reference lists and review articles for additional articles. © 2014 International Society on Thrombosis and Haemostasis

We used a hierarchical strategy to identify eligible articles. One of the authors (E.V.) screened all the titles. Independently, two authors (A.S. and E.V.S.F.) reviewed exclusive random samples of excluded titles to validate their exclusion. Each random sample was composed of 10% of the excluded titles. Two authors (E.V. and A.S.) independently evaluated the abstracts of all remaining articles for potential inclusion. A thirrd author (E.V.S.F.) resolved conflicts of opinion. Using the same process, we evaluated the full text of the remaining articles to derive the final list of eligible articles. Data abstraction

Data were abstracted by two of the three authors (E.V., A.S., and E.V.S.F.) independently. Conflicts of opinion were resolved by discussion. We abstracted the characteristics of the study, the population, and the CVC. We classified CVCs as non-tunneled, tunneled, umbilical, or peripherally inserted [10]. A non-tunneled CVC is a catheter inserted percutaneously into central veins. A tunneled CVC is a catheter implanted into the central vein with or without a subcutaneous port. An umbilical catheter is inserted in the umbilical vein. A peripherally inserted CVC is inserted percutaneously in a peripheral vein and includes percutaneous CVCs. We also classified CVCs according to the site of insertion. CVCs in the upper or lower extremities included those inserted in veins in or above the heart, or below the heart, respectively. Umbilical CVCs were classified separately. For each article with data on the frequency of CVCrelated DVT, we abstracted the number of patients who underwent surveillance for CVC-related DVT, the number of patients with CVC-related DVT, and the radiologic imaging used to detect CVC-related DVT. We evaluated each study for blinded assessment of DVT. For the RCTs on thromboprophylaxis, we further abstracted data on critical areas in the design and conduct of the RCT. These included the intervention evaluated, assumptions made in calculating the sample size, and recruitment rate, defined as the proportion of eligible patients enrolled in the study. We assessed the quality of the RCTs under the following domains: allocation concealment, blinding of investigators, blinding of outcome assessors, and completeness of data on DVT. We contacted the authors for any missing data elements. Data synthesis and analysis

The presence of CVC-related DVT at any time during the study period was the primary outcome measure. We defined CVC-related DVT as a thrombus extending from the CVC into the lumen of the deep vein where the CVC was inserted, diagnosed with radiologic imaging, regardless of symptoms. Our unit of analysis was the individual

1098 E. Vidal et al 224 articles identified from MEDLINE

124 articles identified from EMBASE

347 articles identified from Cochrane

1956 articles identified from Web of Science

2651 articles retrieved for evaluation 287 duplicate articles excluded 2364 articles screened based on title 1757 articles excluded based on title 756 not in children 487 not related to CVCs 415 DVT not an outcome 99 not a cohort study or RCT

607 articles screened based on abstract 388 articles excluded based on abstract 212 not in children 81 not related to CVCs 50 DVT not an outcome 45 not a cohort study or RCT 219 full-text articles evaluated for eligibility 182 full-text articles excluded 63 not in children 46 DVT not an outcome 37 not related to CVCs 15 no active radiologic surveillance 13 not a cohort study or RCT 8 studies with multiple publications

37 articles included in the meta-analysis 37 studies on the frequency of CVC-related DVT 10 RCTs on thromboprophylaxis against CVC-related DVT Fig. 1. Study selection. CVC, central venous catheter; DVT, deep vein thrombosis; RCT, randomized controlled trial.

patient. We expressed the frequency of CVC-related DVT as the proportion of patients with DVT. To determine the pooled frequency of CVC-related DVT, we combined data from cohort studies and the control arms of RCTs. We also calculated the pooled frequency of CVC-related DVT according to the type and site of insertion of the CVC. We combined RCTs with similar interventions, and calculated the pooled risk ratios (RRs). We assessed statistical heterogeneity with the I2 statistic [11]. This statistic is defined as the percentage of total variation across studies that is attributable to heterogeneity rather than chance. We used the random effects model because, a priori, we hypothesized that there are significant differences in the population, exposures and design among studies. We used the method of DerSimonian and Laird to calculate the pooled frequencies and RRs [12]. All statistical analyses were performed with STATA 13 (StataCorp, College Station, TX, USA).

Results Frequency of CVC-related DVT

From 2651 potential articles, we analyzed 37 articles with a total of 3128 patients (Fig. 1). Of these, 26 were cohort studies and 11 were RCTs (Table 1). Each study included, on average, 85 patients (range, 13–645). A total of 14 studies recruited only newborns, and the rest recruited patients of varying ages. Most of the studies (21/37; 56.8%) recruited critically ill patients admitted to the pediatric or neonatal intensive care unit. Ultrasonography was used in 27 (73.0%) studies to diagnose DVT. Outcome assessors were blinded in 19 of 21 studies with data on blinding. The pooled frequency of CVC-related DVT was 0.20 (95% confidence interval [CI] 0.16–0.24) (Fig. 2). The heterogeneity was high (I2 = 91.4%). The frequency of DVT © 2014 International Society on Thrombosis and Haemostasis

© 2014 International Society on Thrombosis and Haemostasis

Prospective cohort

Prospective Prospective Prospective Prospective

Prospective cohort Prospective cohort

Prospective cohort

Prospective cohort Prospective cohort Randomized controlled trial

Randomized controlled trial Prospective cohort Prospective cohort

Randomized controlled trial

Randomized controlled trial

Prospective cohort

Randomized controlled trial Randomized controlled trial Prospective cohort Randomized controlled trial

Tanke (1994) [41]

Krafte-Jacobs (1995) [42] Shefler (1995) [43] DeAngelis (1996) [44] Nowak-Gottl (1997) [45]

Schwartz (1997) [46] Beck (1998) [47]

Medeiros (1998) [48]

Boo (1999) [49] Knofler (1999) [50] Pierce (2000) [13]

Jacobs (2001) [22]

Massicotte (2003) [19]

Mitchell (2003) [21]

Price (2004) [9]

Butler-O’Hara (2006) [53]

Dubois (2007) [54] Shah (2007) [17]

Ruud (2006) [20]

Kim (2001) [51] Roy (2002) [52]

Randomized controlled trial Prospective cohort Prospective cohort Retrospective cohort Prospective cohort

Smith (1991) [15] Mehta (1992) [37] Yadav (1993) [38] Dollery (1994) [39] Pippus (1994) [40]

cohort cohort cohort cohort

Study design

Author (year)

Hospitalized Critically ill

Malignancy

Congenital bleeding disorder Critically ill

Malignancy

Hospitalized

Critically ill Critically ill

Critically ill

Congenital bleeding disorder Critically ill Malignancy Critically ill

Critically ill Critically ill Critically ill Congenital heart disease and hospitalized Critically ill Critically ill

Critically ill

Malignancy Critically ill Critically ill Parenteral nutrition Critically ill

Patient population

0–18 Newborn

0–18

Newborn

0–7

6–18

0–18

Newborn Newborn

0–6

Newborn 0–18 0–16

0–18

Newborn 0–18

0–8 0–16 0–18 0–18

Newborn

0–18 Newborn Newborn 0–18 Newborn

Age group (years)

Peripherally inserted Peripherally inserted

Umbilical and peripherally inserted Tunneled

Tunneled

Tunneled, non-tunneled, peripherally inserted, and umbilical Tunneled

Umbilical Umbilical

Non-tunneled

Umbilical Tunneled Non-tunneled

Tunneled

Umbilical Non-tunneled

Non-tunneled Non-tunneled Non-tunneled Non-tunneled and tunneled

Tunneled Tunneled Umbilical Tunneled Tunneled and peripherally inserted Umbilical

Type of CVC

Table 1 Characteristics of included studies for the frequency of central venous catheter (CVC)-related deep vein thrombosis

Upper extremity Upper and lower extremities

Umbilicus, upper and lower extremities Upper extremity

Upper extremity

Upper extremity

Upper and lower extremities

Umbilicus Umbilicus

Umbilicus Upper extremity Upper and lower extremities Lower extremity

Umbilicus Upper and lower extremities Upper extremity

Upper extremity Upper extremity Umbilicus Upper extremity Upper and lower extremities Umbilicus, upper and lower extremities Lower extremity Lower extremity Lower extremity Upper and lower extremities

Site of insertion

Ultrasound Ultrasound

Ultrasound

Ultrasound, venography, and magnetic resonance imaging Ultrasound and venography Echocardiography

Ultrasound Echocardiography and venography Venography

Ultrasound

Ultrasound Ultrasound Ultrasound

Venography

Ultrasound Ultrasound

Ultrasound Ultrasound Ultrasound Ultrasound

Echocardiography

Echocardiography Echocardiography Ultrasound Echocardiography Ultrasound

Method of diagnosis

NR Yes

Yes

Yes

Yes

Yes

Yes

NR Yes

NR

No No Yes

NR

NR NR

Yes NR Yes NR

Yes

NR NR NR Yes NR

Blinding of outcome assessor

Catheter-related thrombosis in children 1099

Prospective cohort Prospective cohort Prospective cohort

Randomized controlled trial Randomized controlled trial Retrospective cohort

Turebylu (2007) [55] Chung (2008) [8] Hanslik (2008) [56]

Anton (2009) [14]

Prospective cohort

Retrospective cohort

Faustino (2013) [60]

Haddad (2014) [61]

NR, not reported.

Albisetti (2013) [59]

Prospective cohort Randomized controlled trial Prospective cohort

Gharehbaghi (2011) [58] Unal (2012) [16]

Cost (2011) [57]

Schroeder (2010) [18]

Study design

Author (year)

Table 1 (Continued)

Critically ill

Critically ill

Malignancy

Congenital heart disease Congenital heart disease Congenital bleeding disorder Critically ill Critically ill

Critically ill Malignancy Congenital heart disease

Patient population

Newborn

0–18

0–18

Newborn Newborn

0–18

0–1

0–1

Newborn 0–18 0–18

Age group (years)

Umbilical and tunneled

Non-tunneled

Tunneled

Umbilical Umbilical

Tunneled

Non-tunneled

Non-tunneled

Umbilical Tunneled Non-tunneled

Type of CVC

Upper and lower extremities Umbilicus and upper extremity

Upper extremity

Umbilicus Umbilicus

Upper and lower extremities Upper and lower extremities Upper extremity

Umbilicus Upper extremity Upper extremity

Site of insertion

Ultrasound

Ultrasound and venography Ultrasound

Ultrasound Venography Echocardiography, ultrasound, and venography Ultrasound and venography Echocardiography and ultrasound Ultrasound and venography Ultrasound Echocardiography

Method of diagnosis

Yes

Yes

NR

Yes Yes

NR

Yes

Yes

NR NR Yes

Blinding of outcome assessor

1100 E. Vidal et al

© 2014 International Society on Thrombosis and Haemostasis

Catheter-related thrombosis in children 1101

AUTHOR

YEAR

NUMBER OF NUMBER OF PATIENTS DVT

FREQ (95% Cl) 0.14 (–0.04, 0.33) 0.14 (0.04, 0.25) 0.32 (0.12, 0.51) 0.39 (0.22, 0.56) 0.46 (0.31, 0.60) 0.13 (0.08, 0.18) 0.44 (0.25, 0.63) 0.11 (0.03, 0.19) 0.15 (–0.01, 0.31) 0.07 (0.03, 0.11) 0.01 (–0.01, 0.03) 0.16 (0.08, 0.24) 0.15 (–0.04, 0.35) 0.04 (–0.02, 0.10) 0.41 (0.18, 0.65) 0.08 (0.03, 0.13) 0.22 (0.05, 0.39) 0.43 (0.33, 0.53) 0.30 (0.17, 0.43) 0.13 (0.05, 0.20) 0.37 (0.24, 0.49) 0.81 (0.62, 1.00) 0.11 (0.07, 0.16) 0.24 (0.10, 0.39) 0.09 (0.05, 0.13) 0.21 (0.12, 0.30) 0.21 (0.06, 0.37) 0.00 (–0.14, 0.14) 0.28 (0.19, 0.37) 0.43 (0.27, 0.58) 0.16 (0.04, 0.28) 0.39 (0.23, 0.55 ) 0.03 (0.00, 0.06) 0.04 (–0.03, 0.11) 0.39 (0.31, 0.48) 0.17 (0.10, 0.25) 0.11 (0.08, 0.13) 0.20 (0.16, 0.24)

Smith 1991 14 2 Mehta 1992 42 6 Yadav 1993 22 7 Dollery 1994 31 12 Pippus 1994 46 21 Tanke 1994 193 25 Krafte-Jacobs 1995 25 11 Shefler 1995 54 6 DeAngelis 1996 20 3 Nowak-Gottl 1997 128 9 Schwartz 1997 100 1 Beck 1998 76 12 Medeiros 1998 13 2 Boo 1999 47 2 Knofler 1999 17 7 Pierce 2000 103 8 Jacobs 2001 23 5 Kim 2001 100 43 Roy 2002 47 14 Massicotte 2003 80 10 Mitchell 2003 60 22 Price 2004 16 13 Butler-O'Hara 2006 210 24 Ruud 2006 33 8 Dubois 2007 214 20 Shah 2007 86 18 Turebylu 2007 28 6 Chung 2008 25 0 Hanslik 2008 90 25 Anton 2009 40 17 Schroeder 2010 37 6 Cost 2011 36 14 Gharehbaghi 2011 164 5 Unal 2012 27 1 Albisetti 2013 114 45 Faustino 2013 103 18 Haddad 2014 645 69 Overall (I-squared = 91.2%, P = 0.000)

% Weight 1.94 2.80 1.83 2.05 2.35 3.40 1.83 3.05 2.21 3.42 3.56 3.07 1.81 3.31 1.50 3.37 2.08 2.90 2.50 3.17 2.61 1.86 3.43 2.33 3.46 3.02 2.26 2.43 2.95 2.25 2.64 2.18 3.53 3.18 2.98 3.16 3.54 100.00

NOTE: Weights are from random effects analysis 0

0.25 0.5 0.75 FREQUENCY

1

Fig. 2. Random effects meta-analysis showing the individual and pooled frequencies of central venous catheter-related deep vein thrombosis (DVT) in children. Squares represent single-study estimates of the frequency, and the diamond represents the pooled frequency. CI, confidence interval.

according to type of CVC was available from 34 articles with 2300 patients. The pooled frequencies of DVT with tunneled, non-tunneled, umbilical and peripherally inserted CVCs were 0.28 (95% CI 0.18–0.38; I2 = 86.8%), 0.18 (95% CI 0.12–0.25; I2 = 82.3%), 0.15 (95% CI 0.08– 0.21; I2 = 91.9%), and 0.14 (95% CI 0.07–0.20; I2 = 67.2%), respectively (Fig. 3). The frequency of DVT according to the site of insertion was available from 32 articles with 1906 patients. The frequency of DVT seemed to be similar between patients with CVCs inserted in the upper and lower extremities (Fig. 4). The pooled frequency of CVC-related DVT in the upper extremity © 2014 International Society on Thrombosis and Haemostasis

was 0.24 (95% CI 0.17–0.31; I2 = 85.8%), and that of CVC-related DVT in the lower extremity was 0.20 (95% CI 0.13–0.27; I2 = 42.8%). Thromboprophylaxis against CVC-related DVT

We analyzed 10 RCTs on thromboprophylaxis (Table 2). These RCTs tested the efficacy of heparin-bonded CVC [13,14], unfractionated heparin [15–18], low molecular weight heparin [19], warfarin [20], antithrombin concentrate [21], and nitroglycerin [22]. Treatment was compared with either standard of care [13–15, 19–21] or placebo

1102 E. Vidal et al NUMBER OF NUMBER OF PATIENTS DVT

FREQ (95% Cl)

% Weight

TUNNELED Smith 1991 14 2 Mehta 1992 42 6 Dollery 1994 31 12 Tanke 1994 63 6 Nowak-Gottl 1997 23 4 Medeiros 1998 13 2 Knofler 1999 17 7 Mitchell 2003 60 22 Price 2004 16 13 Ruud 2006 33 8 Chung 2008 25 0 14 Cost 2011 36 Albisetti 2013 114 45 Subtotal (I-squared = 86.8%, P = 0.000) .

0.14 (–0.04, 0.33) 0.14 (0.04, 0.25) 0.39 (0.22, 0.56) 0.10 (0.02, 0.17) 0.17 (0.02, 0.33) 0.15 (–0.04, 0.35) 0.41 (0.18, 0.65) 0.37 (0.24, 0.49) 0.81 (0.62, 1.00) 0.24 (0.10, 0.39) 0.00 (–0.14, 0.14) 0.39 (0.23, 0.55) 0.39 (0.31, 0.48) 0.28 (0.18, 0.38)

7.17 8.45 7.38 8.87 7.67 6.94 6.27 8.21 7.03 7.81 7.96 7.59 8.66 100.00

NONTUNNELED Krafte-Jacobs 1995 25 11 Shefler 1995 54 6 DeAngelis 1996 20 3 Nowak-Gottl 1997 105 5 Beck 1998 12 76 Pierce 2000 103 8 Jacobs 2001 23 5 Hanslik 2008 90 25 Anton 2009 40 17 Schroeder 2010 37 6 Faustino 2013 103 18 Subtotal (I-squared = 82.3%, P = 0.000) .

0.44 (0.25, 0.63) 0.11 (0.03, 0.19) 0.15 (–0.01, 0.31) 0.05 (0.01, 0.09) 0.16 (0.08, 0.24) 0.08 (0.03, 0.13) 0.22 (0.05, 0.39) 0.28 (0.19, 0.37) 0.43 (0.27, 0.58) 0.16 (0.04, 0.28) 0.17 (0.10, 0.25) 0.18 (0.12, 0.25)

5.73 10.26 7.09 11.90 10.34 11.55 6.63 9.87 7.22 8.69 10.71 100.00

UMBILICAL Yadav 1993 22 7 Tanke 1994 92 16 Schwartz 1997 100 1 Boo 1999 47 2 Kim 2001 100 43 Roy 2002 47 14 Butler-O'Hara 2006 106 10 Turebylu 2007 28 6 Gharehbaghi 2011 164 5 Unal 2012 27 1 Subtotal (I-squared = 91.9%, P = 0.000) .

0.32 (0.12, 0.51) 0.17 (0.10, 0.25) 0.01 (–0.01, 0.03) 0.04 (–0.02, 0.10) 0.43 (0.33, 0.53) 0.30 (0.17, 0.43) 0.09 (–0.09, 0.28) 0.21 (0.06, 0.37) 0.03 (0.00, 0.06) 0.04 (–0.03, 0.11) 0.15 (0.08, 0.21)

6.11 11.19 13.11 12.02 10.27 8.67 6.44 7.73 12.99 11.46 100.00

0.13 (0.07, 0.20) 0.09 (0.05, 0.13) 0.21 (0.12, 0.30) 0.14 (0.07, 0.20)

32.29 42.04 25.68 100.00

AUTHOR

YEAR

PERIPHERALLY INSERTED Butler-O'Hara 2006 104 14 Dubois 2007 214 20 Shah 2007 86 18 Subtotal (I-squared = 67.2%, P = 0.047) NOTE: Weights are from random effects analysis 0

0.25 0.5 0.75 FREQUENCY

1

Fig. 3. Random effects meta-analysis showing the individual and pooled frequencies of central venous catheter-related deep vein thrombosis (DVT) in children by type of catheter. Squares represent single-study estimates of the frequency, and diamonds represent pooled frequencies. CI, confidence interval.

[16–18,22]. All of the RCTs were parallel trials except that by Smith et al. [15], which was a crossover trial (Table 2). Most (6/10; 60.0%) were single-center trials. Half of the trials were not powered for DVT. In those powered for DVT, control event rates used in sample size calculation were set at 0.20–0.44, which were generally higher than those observed in the trial. Relative reductions were hypothesized to be 25–75%. The proportion of

eligible patients recruited ranged from 36.0% in the multicenter trial by Massicotte et al. [19] to 92.0% in the single-center trial by Unal et al. [16]. The quality of the RCTs was generally adequate. Allocation was concealed by the use of sealed opaque envelopes in five trials and computerized algorithms in four trials (Table 2). Investigators were blinded in half of the trials. Outcome assessors were blinded in at least seven © 2014 International Society on Thrombosis and Haemostasis

Catheter-related thrombosis in children 1103

AUTHOR

NUMBER OF NUMBER OF DVT YEAR PATIENTS

FREQ (95% Cl)

% Weight

UPPER EXTREMITY Smith 1991 14 2 Mehta 1992 42 6 Dollery 1994 31 12 Pippus 1994 18 3 Tanke 1994 63 6 Nowak-Gottl 1997 23 4 Beck 1998 53 7 Medeiros 2 1998 13 Knofler 1999 17 7 Mitchell 2003 60 22 Price 2004 16 13 Ruud 2006 33 8 Dubois 2007 214 20 Chung 2008 25 0 Hanslik 2008 90 25 Schroeder 2010 36 6 Cost 2011 36 14 Albisetti 2013 114 45 Faustino 2013 64 13 Subtotal (I-squared = 85.8%, P = 0.000) .

0.14 (–0.04, 0.33) 0.14 (0.04, 0.25) 0.39 (0.22, 0.56) 0.17 (–0.01, 0.34) 0.10 (0.02, 0.17) 0.17 (0.02, 0.33) 0.13 (0.04, 0.22) 0.15 (–0.04, 0.35) 0.41 (0.18, 0.65) 0.37 (0.24, 0.49) 0.81 (0.62, 1.00) 0.24 (0.10, 0.39) 0.09 (0.05, 0.13) 0.00 (–0.14, 0.14) 0.28 (0.19, 0.37) 0.17 (0.04, 0.29) 0.39 (0.23, 0.55) 0.39 (0.31, 0.48) 0.20 (0.10, 0.30) 0.24 (0.17, 0.31)

4.50 5.77 4.70 4.68 6.24 4.97 5.99 4.30 3.73 5.52 4.37 5.12 6.57 5.27 5.97 5.52 4.90 6.01 5.88 100.00

LOWER EXTREMITY Pippus 1994 28 8 Krafte-Jacobs 1995 25 11 Shefler 1995 54 6 DeAngelis 1996 20 3 Beck 1998 5 23 Jacobs 2001 23 5 Schroeder 2010 1 0 Faustino 2013 37 5 Subtotal (I-squared = 42.8%, P = 0.093) .

0.29 (0.12, 0.45) 0.44 (0.25, 0.63) 0.11 (0.03, 0.19) 0.15 (–0.01, 0.31) 0.22 (0.05, 0.39) 0.22 (0.05, 0.39) 0.00 (–0.97, 0.97) 0.14 (0.02, 0.25) 0.20 (0.13, 0.27)

11.95 9.78 22.55 12.97 11.83 11.83 0.55 18.54 100.00

0.32 (0.12, 0.51) 0.17 (0.10, 0.25) 0.01 (–0.01, 0.03) 0.04 (–0.02, 0.10) 0.43 (0.33, 0.53) 0.30 (0.17, 0.43) 0.09 (–0.09, 0.28) 0.21 (0. 06, 0.37) 0.03 (0.00, 0.06) 0.04 (–0.03, 0.11) 0.15 (0.08, 0.21)

6.11 11.19 13.11 12.02 10.27 8.67 6.44 7.73 12.99 11.46 100.00

UMBILICUS Yadav 1993 22 7 Tanke 1994 92 16 Schwartz 1997 100 1 Boo 1999 47 2 Kim 2001 100 43 Roy 2002 47 14 Butler-O'Hara 2006 106 10 Turebylu 2007 28 6 Gharehbaghi 2011 164 5 Unal 2012 27 1 Subtotal (I-squared = 91.9%, P = 0.000) NOTE: Weights are from random effects analysis 0

0.25 0.5 0.75 FREQUENCY

1

Fig. 4. Random effects meta-analysis showing the individual and pooled frequencies of central venous catheter-related deep vein thrombosis (DVT) in children by site of insertion of the catheter. Squares represent single-study estimates of the frequency, and diamonds represent pooled frequencies. CI, confidence interval.

trials, including three open trials. The results of the trials, however, may have been compromised by the amount of missing data on DVT. The most common reason was the inability to obtain radiologic imaging. On average, 10.7% of patients recruited did not have data on DVT. In seven trials, outcome data were missing for at least 5% of the patients. We did not find a reduction in the frequency of CVCrelated DVT with the interventions tested (Fig. 5). Only © 2014 International Society on Thrombosis and Haemostasis

half of the trials were completed. Four trials were terminated early for futility, and one for poor recruitment. We conducted meta-analyses for heparin-bonded CVC and unfractionated heparin, because more than one study evaluated their efficacy. Pierce et al. showed a reduction in the frequency of DVT with heparin-bonded CVCs [13]. However, when the data were pooled, the RR with heparinbonded CVC was not significant (RR 0.34; 95% CI 0.01– 7.68). The heterogeneity between these two trials was high

4

Shah (2007) [17]

UFH

UFH

HBC

UFH

Warfarin

Low molecular weight heparin Antithrombin concentrate

Nitroglycerin

UFH HBC

Intervention

50% reduction from 40% 75% reduction from 20% NR

25% reduction from 27% NR

75% reduction from 40% 40% reduction from 25% NR

NR NR

92.0

58.0

53.6

71.7

86.9

NR

36.0

NR

NR NR

Recruitment rate (%)†

Sealed opaque envelope

Computer algorithm

Sealed opaque envelope

Computer algorithm

Sealed opaque envelope

Computer algorithm

Computer algorithm

Sealed opaque envelope

NR Sealed opaque envelope

Allocation concealment

Yes

Yes

Yes

Yes

No

Yes

No

Yes

NR Yes

Blinding of investigators

Yes

Yes

Yes

Yes

Yes

Yes

Yes

NR

NR Yes

Blinding of outcome assessor

0

10.9

10.3

12.8

15.1

22.0

15.1

17.0

0 4.3

Patients not assessed for DVT(%)‡

Completed; not powered for reduction in DVT frequency

Stopped for futility

Completed; not powered for reduction in DVT frequency Stopped for futility

Stopped for poor recruitment Completed; not powered for reduction in DVT frequency Stopped for futility

Completed Completed; not powered for reduction in DVT frequency Stopped for futility

Comments

HBC, heparin-bonded catheter; NR, not reported; UFH, unfractionated heparin. *Hypothesized relative reduction in DVT frequency from the control event rate. †Proportion of eligible patients enrolled in the study. ‡Proportion of randomized patients who were not assessed for DVT.

1

2

Ruud (2006) [20]

Unal (2012) [16]

9

Mitchell (2003) [21]

1

20

Massicotte (2003) [19]

Schroeder (2010) [18]

1

Jacobs (2001) [22]

1

1 1

Smith (1991) [15] Pierce (2000) [13]

Anton (2009) [14]

Centers

Author (year)

Sample size calculation*

Table 2 Characteristics of included randomized controlled trials on thromboprophylaxis against central venous catheter-related deep vein thrombosis (DVT)

1104 E. Vidal et al

© 2014 International Society on Thrombosis and Haemostasis

Catheter-related thrombosis in children 1105

AUTHOR

YEAR

TREATMENT (n/N)

CONTROL (n/N)

FREQ (95% Cl)

% Weight

HEPARIN-BONDED CVC 2000 0/97 8/103 Pierce 21/47 17/40 Anton 2009 Subtotal (I-squared = 79.6%, P = 0.027) .

0.06 (0.00, 1.07) 1.05 (0.65, 1.70) 0.34 (0.01, 7.68)

40.37 59.63 100.00

1.00 (0.07, 14.45) 0.95 (0.53, 1.69) 0.93 (0.35, 2.46) 0.47 (0.02, 10.88) 0.93 (0.57, 1.51)

3.30 69.35 24.97 2.38 100.00

1.13 (0.51, 2.50) 1.13 (0.51, 2.50)

100.00 100.00

0.85 (0.34, 2.17) 0.85 (0.34, 2.17)

100.00 100.00

0.76 (0.38, 1.55) 0.76 (0.38, 1.55)

100.00 100.00

1.53 (0.57, 4.10)

100.00

1.53 (0.57, 4.10)

100.00

UNFRACTIONATED HEPARIN Smith 1991 1/14 1/14 Shah 18/91 18/86 2007 Schroeder 2010 8/53 6/37 0/19 1/27 Unal 2012 Subtotal (I-squared = 0.0%, P = 0.979) . LOW MOLECULAR WEIGHT HEPARIN Massicotte 2003 11/78 10/80 Subtotal (I-squared = 0.0%, P = 0.0) . WARFARIN Ruud 6/29 8/33 2006 Subtotal (I-squared = 0.0%, P = 0.0) . ANTITHROMBIN CONCENTRATE 7/25 22/60 Mitchell 2003 Subtotal (I-squared = 0.0%, P = 0.0) . NITROGLYCERIN Jacobs

2001

7/21

5/23

Subtotal (I-squared = 0.0%, P = 0.0) NOTE: Weights are from random effects analysis

0.01

0.1 TREATMENT

1

10 CONTROL

100

Fig. 5. Random effects meta-analysis showing the effects of different agents on the risk of central venous catheter (CVC)-related deep vein thrombosis in children. Squares represent single-trial estimates, and diamonds represent pooled trial effects. CI, confidence interval; RR, risk ratio.

(I2 = 79.6%). Likewise, intravenous unfractionated heparin was not associated with a reduction in the frequency of DVT (RR 0.93; 95% CI 0.57–1.51). The doses of heparin used were 50 units twice daily [15], 0.5 units h 1 [16], 0.5 units kg 1 h 1 [17], and 10 units kg 1 h 1 [18]. Despite different doses, the heterogeneity among the trials was low (I2 = 0.0%). Discussion This is the first meta-analysis on the frequency of and thromboprophylaxis against CVC-related DVT in children. We report that one in five children with CVCs experienced CVC-related DVT. DVT seems to be least common with umbilical and peripherally inserted CVCs. The frequency of DVT seems to be similar between CVCs © 2014 International Society on Thrombosis and Haemostasis

in the upper and lower extremities. We did not find evidence that heparin-bonded CVCs, unfractionated heparin, low molecular weight heparin, warfarin, antithrombin concentrate or nitroglycerin reduced the risk of CVCrelated DVT. There was adequate blinding and allocation concealment in the RCTs that we analyzed. However, inadequate power and missing outcome data may have compromised the results. The frequency of CVC-related DVT of 0.20 in our study is slightly higher than that in adults. In recent RCTs, 14–18% of adults who underwent active surveillance for DVT with radiologic imaging had CVC-related DVT [23]. Children, in general, have lower risks for DVT than adults, owing to biological differences in coagulation, vasculature, and lifestyle [6]. The higher frequency of CVC-related DVT in children may be related to a

1106 E. Vidal et al

higher CVC/vein ratio in children causing flow stasis because of mechanical obstruction [24]. The type and site of insertion of the CVC are potentially modifiable factors for DVT. DVT seems to be least common with umbilical and peripherally inserted CVCs. In cases in which the type of CVC can be selected, our study suggests that peripherally inserted CVCs may be preferred. Our results, however, contrast with data from adults. Peripherally inserted CVCs are associated with a higher risk of DVT than tunneled CVCs in adults with malignancy [25] and non-tunneled CVCs in adults with critical illness [26–28]. Inclusion of only clinically apparent DVT in the adult studies [25–27] may partly explain the difference from our findings. The indication for the CVC may also explain the discrepancy. The frequencies of DVT in children with CVCs in the upper and lower extremities seem to be similar. In adults, CVC-related DVT in the subclavian vein is as common as that in the internal jugular vein, but less common than those in the femoral veins [29]. We do not have data on DVT specific to these veins to determine whether a similar pattern exists in children. We did not find evidence that thromboprophylaxis reduced the risk of CVC-related DVT in children. Although thromboprophylaxis prevents unprovoked DVT in adults [2], its role against CVC-related DVT is unclear. In a meta-analysis by Akl et al., unfractionated heparin, low molecular heparin and warfarin were not associated with reductions in the frequency of CVC-related DVT in adults with malignancy [30]. In contrast, Kirkpatrick et al. showed significant reductions in the frequency of CVC-related DVT with the same agents in adults with and without malignancy [31]. The quality of the RCTs in our meta-analysis was strengthened by adequate allocation concealment and blinding. Certain issues, however, may have compromised their results. Most of the trials were underpowered. Half were not powered for thrombosis, and half were not completed. Futility was the most common reason for early termination of the trials. Futility suggests that the hypothesized reduction in the frequency of DVT could not be achieved despite the calculated sample size being achieved. The hypothesized reductions in these trials, however, were probably too large, with one trial aiming to detect a 75% relative reduction in the frequency of DVT [18]. These reductions in the frequency of DVT are probably unachievable in children. The magnitude of reduction in outcomes in children is more likely to be moderate at best, with a relative reduction of 25–30% [32]. Only Ruud et al. used a reduction in the frequency of DVT within this range [20]. In addition, the control event rates used in calculating the sample size were overestimated. This further decreased the power of the studies. The majority of the RCTs have > 5% of patients without data on DVT. The most common reason for missing outcome data was the inability to obtain radiologic

imaging. Exclusion of these patients from the analysis may have affected the validity of the results. Such missing data may lead to a biased and imprecise estimate of the treatment effect. Although there are no universally accepted thresholds, < 5% missing data does not usually affect the quality of the RCT [33]. However, bias and imprecision increase as the proportion of missing data increases. More than 20% missing data is usually deemed to be unacceptable. The timing of thromboprophylaxis may partly explain the lack of efficacy of thromboprophylaxis against CVCrelated DVT in children. Pierce et al. showed a significant reduction in the frequency of CVC-related DVT with heparin-bonded CVC when thromboprophylaxis was started upon insertion of the CVC [13]. With low molecular weight heparin started, on average, 2.6 days after insertion of the CVC, Massicotte et al. failed to show a reduction in the frequency of CVC-related DVT [19]. The timing of thromboprophylaxis was unclear in the other RCTs that tested systemic agents. The dose of the agent may also be important. In a prospective cohort study, Newall et al. suggested a reduction in the frequency of clinically apparent CVC-related DVT with therapeutic, instead of prophylactic, doses of warfarin [34]. The frequency of CVC-related DVT in children, the lack of efficacy of the interventions tested and the limitations of previously conducted RCTs on thromboprophylaxis in children necessitate the conduct of well-designed RCTs. With a moderate reduction of 30%, a control event rate of 20%, and power of 80%, a two-armed RCT with equal allocation will need at least 1230 patients. We selected a 30% reduction in the frequency of CVC-related DVT on the basis of the typical magnitude of effect sizes of treatments in children [32] and on a recently completed thromboprophylaxis RCT in critically ill adults [35]. Adjustment for the type of CVC may be needed. Multiple centers are needed to complete this trial in a timely manner. Since the largest pediatric multicenter trial on thromboprophylaxis was terminated early because of poor recruitment [19], measures should be instituted to maximize recruitment. Measures to minimize missing outcome data should also be implemented. A pilot trial to better understand how to maximize recruitment and minimize missing data is highly recommended to enhance the success of the full-scale RCT. Finally, the choice of intervention is important. Because heparin-bonded CVCs reduced the frequency of DVT in a single-center RCT [13], the multicenter Catheters in Children trial will confirm whether CVC-related DVT is less common with heparinbonded CVCs than with regular CVCs [36]. The trial has completed recruitment, and the results are eagerly awaited. Novel anticoagulants, such as direct factor Xa inhibitors and direct thrombin inhibitors, should also be investigated. Our study has several strengths. We included broad terms in our search to minimize selection bias. We © 2014 International Society on Thrombosis and Haemostasis

Catheter-related thrombosis in children 1107

included articles in foreign languages, conference abstracts, and reference lists. These increase the generalizability of our results. We evaluated each article independently and in duplicate. We included studies that performed active surveillance of all patients with radiologic imaging to obtain an accurate estimate of the frequency of CVC-related DVT. The frequency of CVCrelated DVT based on clinically apparent cases alone underestimates the true frequency of DVT because of the difficulty in identifying the signs and symptoms of DVT [6]. The large number of studies and the large number of patients recruited for these studies increase the precision of our estimates of the frequency of DVT. Our study should also be viewed in light of certain limitations. The heterogeneity among the studies was high, even within the groups analyzed. Other factors, such as patient age and diagnosis, the indication for the CVC, and the radiologic imaging method used, may effect the risk of CVC-related DVT [6]. A patient-level data metaanalysis [25], which was not possible in our study, could adjust for these confounders. Some of the data elements, particularly on blinding of the outcome assessors, were missing, despite attempts to obtain them from the authors. Other limitations of any observational study, such as biases and measurement error, should also be considered in the interpretation of our results. Finally, the number of RCTs on thromboprophylaxis and the number of patients recruited in these RCTs were small.

revision of the intellectual content, and final approval of the manuscript. E. V. S. Faustino contributed substantially to the concept and design, acquisition and interpretation of the data, critical writing, and final approval of the manuscript. Acknowledgements This publication was made possible by CTSA Grants UL1 TR000142 and KL2 TR000140 from the National Center for Research Resources and the National Center for Advancing Translational Science, components of the National Institutes of Health (NIH), and NIH roadmap for Medical Research. Its contents are solely the responsibility of the authors, and do not necessarily represent the official view of the NIH. Disclosure of Conflict of Interests The authors state that they have no conflict of interest. Supporting information Additional Supporting Information may be found in the online version of this article: Data S1. Database search terms and strategy. References

Conclusions Nearly one in five children with CVCs experienced CVCrelated DVT. We did not find evidence that thromboprophylaxis reduced the frequency of CVC-related DVT in children. The RCTs were either not powered for DVT or were powered to detect large reductions in the frequency of DVT. The results of the RCTs may also have been compromised by missing data on DVT. An adequately powered RCT that can detect a modest, clinically significant reduction in the frequency of DVT is needed to determine the efficacy of thromboprophylaxis against CVC-related DVT in children. Because a significant number of patients are needed to conduct such a trial, multiple centers will be needed to complete this trial in a timely manner. Measures to minimize missing data should also be implemented in the conduct of this trial. Addendum E. Vidal contributed substantially to the concept and design, acquisition of data, revision of the intellectual content, and final approval of the manuscript. A. Sharathkumar contributed substantially to the acquisition and interpretation of data, critical writing and final approval of the manuscript. J. Glover contributed substantially to the concept and design, acquisition of data, © 2014 International Society on Thrombosis and Haemostasis

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