Accepted Article
Received Date : 02-Dec-2014 Accepted Date : 11-Dec-2014 Article type
: Letter - to the Editor
Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis: discussion
Male C1 O’Brien S2
Rodriguez, V 3
Mitchell LG4
1
Department of Paediatrics, Medical University of Vienna, Vienna, Austria
2
The Research Institute at Nationwide Children's Hospital, Columbus, USA
3
Mayo Clinic Children’s Center, Mayo Clinic, Rochester, USA
4
University of Alberta, Edmonton, Canada
Corresponding author: LG Mitchell 403 Heritage Medical Research Centre University of Alberta Edmonton, Alberta Canada
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/jth.12818 This article is protected by copyright. All rights reserved.
Accepted Article
Phone number: 7804923137 Fax number: 7804923550 [email protected]
We read with interest the recently published paper by Vidal et al. (1) in this journal. The paper is an important contribution to the literature and we applaud the authors for their work. The high incidence of central venous catheter (CVC)-related deep vein thrombosis (DVT) in children and the limitations of current evidence regarding the benefit-risk balance of thromboprophylaxis as revealed by the meta-analysis, provides rationale for embarking on well-designed trials to determine the safety and efficacy of anticoagulation for primary prevention of DVT in children requiring a CVC.
The Jones et al response letter to the above article disagrees with the conclusions of the study by Vidal et al and state that we are not ready yet for such trials.(2) Their argument is based on two points, one that there is a lack of evidence of clinical relevance of asymptomatic DVT in children and second, that there is a risk of bleeding up to 56%. We are writing to state that we disagree with the arguments put forward by Jones et al and we believe that these trials need to move forward quickly.
First, there is some scientific evidence of the clinical relevance of asymptomatic CVC related DVT. Clinical diagnosis of DVT is insensitive and nonspecific and whether a DVT is detected or remains asymptomatic depends on the underlying disease and clinical awareness.(3) There is no convincing evidence that symptomatic DVT are more relevant than asymptomatic DVT, but we do have evidence from the PARKAA study that the degree of venous occlusion was similar between asymptomatic and symptomatic DVT.(4) There are significant acute clinical problems both with asymptomatic DVT and symptomatic DVT as evidenced by an increased requirement for multiple replacements of CVCs when compared to non DVT controls.(5) Of note, the risk for increased requirement for CVC replacement was similar for symptomatic DVT (odds ratio 5.1 95% CI 2.2,11.7) and asymptomatic DVT (odds ratio 5.5 95% CI 1.05,29). These data indicate asymptomatic and symptomatic DVT have comparable risk for CVC loss due to significant venous occlusion. In addition, long term sequelae, such as post thrombotic syndrome has been observed in comparable frequencies after asymptomatic DVT and symptomatic DVT by several studies (6-8)
This article is protected by copyright. All rights reserved.
Accepted Article
In the letter by Jones et al, the bleeding event rate for heparin therapy in children is stated as being up to 56%, however, that bleeding rate was in fact reported from older adult treatment studies. The authors make reference to a pediatric study with unfractionated heparin given at therapeutic doses to critically ill patients, but the bleeding rate was actually 24% in a very high risk population.(9) Pertinent to the discussion here, the dosage for pediatric prophylactic anticoagulation would be considerably lower than for treatment. In terms of the bleeding event rate in primary prophylaxis studies, the best data are from the PROTEKT trial, in which the rate of major bleeding was 1% in the non-anticoagulant/standard of care arm and 0% in the prophylaxis arm using low molecular weight heparin.(10) Of note, use of new oral anticoagulants has the potential for lower risk of bleeding. The optimal way to establish the bleeding event rate and the risk benefit ratio of primary prophylaxis is through randomised controlled clinical trials with standardised outcome definitions for bleeding and DVT.(11)
While we agree that there is a need for prospectively collected long term follow up, we are convinced that the most valid and efficient way to assess both the effect of thromboprophylaxis as well as long-term relevance of symptomatic versus asymptomatic DVT would be interventional randomised controlled trial followed by long-term follow-up. We also agree that there is a growing movement for institutions, and increasing internal and external pressures on hematologists, to develop their own thromboprophylaxis clinical guidelines based on no or little evidence. The urgency around this topic highlights that prevention of DVT in children is an important clinical goal and the development of CVC
related DVT is viewed as suboptimal clinical care. In the absence of good evidence, health care providers are left with adopting unproven practices in the best efforts to manage their patients. Importantly, as these non-evidence based guidelines become standard of care, the opportunity to do any properly designed clinical trials will be lost, as, based on no or little evidence, equipoise on the issue will no longer exist. We argue there is a need for appropriately designed clinical trials as basis for best practice guidelines and any further delay in implementing these trials will only lead to more non-evidence based changes in practice. Finally, we challenge the statement by Jones et al that “‘…Early detection and treatment of thrombosis may well be a safer and more effective option than widespread
This article is protected by copyright. All rights reserved.
Accepted Article
thromboprophylaxis, given the risk benefit ratio of anticoagulation of sick children is also uncertain…’” Waiting for occlusion to occur means the child now requires full-dose anticoagulation over several months, is at risk of acute complications such as loss of venous access, has the potential for non-resolution of the DVT, as well as risk for DVT recurrence and post thrombotic syndrome. This scenario seems to have many disadvantages compared to preventing a DVT a priori, if primary prophylaxis is shown to be efficacious and safe in clinical trials.
Addendum The first draft of the letter was written by C. Male and L. G. Mitchell, with subsequent and final drafts written by all four authors. All authors reviewed and approved the final version.
Conflict of Interest L. G. Mitchell reports personal fees from Boehringer Ingleheim; grants and personal fees from Bristol Myers Squibb, outside the submitted work; and is a member of the Steering Committee for the AESOP trial (Apixaban prEventionS of thrOmbosis in Pediatrics) which is trial assessing primary prophylaxis with anticoagulation for prevention of deep vein thrombosis in children with central venous lines. V. Rodriguez served as co Principal Investigator in a study on Apixaban for the Children's Oncology Group sponsored by Bristol Myers Squib, outside the submitted work S. O'Brien served as the Principal Investigator in a study on DVT prophylaxis in children with leukaemia for the Children's Oncology Group sponsored by for a Bristol Myers, outside the submitted work. C. Male served on steering committees for Bristol-Myers-Squibb and Bayer, outside the submitted work. Reference List (1) Vidal E, Sharathkumar A, Glover J, Faustino EV: Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis. J Thromb Haemost 2014; 12:1096. (2) Jones S, Ignjatovic V, Monagle P, Newall F: Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis: comment. J Thromb Haemost 2014.
This article is protected by copyright. All rights reserved.
Accepted Article
(3) Male C, Kuhle S, Mitchell L: Diagnosis of venous thromboembolism in children. Semin Thromb Hemost 2003; 29:377. (4) Mitchell LG, Andrew M, Hanna K, Abshire T, Halton J, Anderson R, Cherrick I, Desai S, Mahoney D, McCuster P, Wu J, Dahl G, Chait P, de VG, Lee KJ, Mikulis D, Ginsberg J, Way C: A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with L-asparaginase: results of the Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) Study. Cancer 2003; 97:508.
(5) Kulkarni K, Halton J, Spavor M, Israels SJ, Abish S, Yong J, Yasui Y, Mitchell LG: Increased requirement for central venous catheter replacement in paediatric oncology patients with deep venous thrombosis: A multicentre study. Thromb Haemost 2014; 113. (6) Kuhle S, Spavor M, Massicotte P, Halton J, Cherrick I, Dix D, Mahoney D, Bauman M, Desai S, Mitchell LG: Prevalence of post-thrombotic syndrome following asymptomatic thrombosis in survivors of acute lymphoblastic leukemia. J Thromb Haemost 2008; 6:589.
(7) Van Ommen CH, Ottenkamp J, Lam J, Brennickmeier M, Heijmans HS, Buller HR, Peters M: The risk of postthrombotic syndrome in children with congenital heart disease. J Pediatr 2002; 141:582. (8) Polen E, Weintraub M, Stoffer C, Jaffe DH, Burger A, Revel-Vilk S: Post-thrombotic syndrome after central venous catheter removal in childhood cancer survivors: A prospective cohort study. Pediatr Blood Cancer 2014 (9) Kuhle S, Eulmesekian P, Kavanagh B, Massicotte P, Vegh P, Mitchell LG: A clinically significant incidence of bleeding in critically ill children receiving therapeutic doses of unfractionated heparin: a prospective cohort study. Haematologica 2007; 92:244.
(10) Massicotte P, Julian JA, Gent M, Shields K, Marzinotto V, Szechtman B, Chan AK, Andrew M: An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial. Thromb Res 2003; 109:101.
(11) Mitchell LG, Goldenberg NA, Male C, Kenet G, Monagle P, Nowak-Gottl U: Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children. J Thromb Haemost 2011; 9:1856.
This article is protected by copyright. All rights reserved.
Received Date : 02-Dec-2014 Accepted Date : 11-Dec-2014 Article type
: Letter - to the Editor
Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis: discussion
Male C1 O’Brien S2
Rodriguez, V 3
Mitchell LG4
1
Department of Paediatrics, Medical University of Vienna, Vienna, Austria
2
The Research Institute at Nationwide Children's Hospital, Columbus, USA
3
Mayo Clinic Children’s Center, Mayo Clinic, Rochester, USA
4
University of Alberta, Edmonton, Canada
Corresponding author: LG Mitchell 403 Heritage Medical Research Centre University of Alberta Edmonton, Alberta Canada
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/jth.12818 This article is protected by copyright. All rights reserved.
Accepted Article
Phone number: 7804923137 Fax number: 7804923550 [email protected]
We read with interest the recently published paper by Vidal et al. (1) in this journal. The paper is an important contribution to the literature and we applaud the authors for their work. The high incidence of central venous catheter (CVC)-related deep vein thrombosis (DVT) in children and the limitations of current evidence regarding the benefit-risk balance of thromboprophylaxis as revealed by the meta-analysis, provides rationale for embarking on well-designed trials to determine the safety and efficacy of anticoagulation for primary prevention of DVT in children requiring a CVC.
The Jones et al response letter to the above article disagrees with the conclusions of the study by Vidal et al and state that we are not ready yet for such trials.(2) Their argument is based on two points, one that there is a lack of evidence of clinical relevance of asymptomatic DVT in children and second, that there is a risk of bleeding up to 56%. We are writing to state that we disagree with the arguments put forward by Jones et al and we believe that these trials need to move forward quickly.
First, there is some scientific evidence of the clinical relevance of asymptomatic CVC related DVT. Clinical diagnosis of DVT is insensitive and nonspecific and whether a DVT is detected or remains asymptomatic depends on the underlying disease and clinical awareness.(3) There is no convincing evidence that symptomatic DVT are more relevant than asymptomatic DVT, but we do have evidence from the PARKAA study that the degree of venous occlusion was similar between asymptomatic and symptomatic DVT.(4) There are significant acute clinical problems both with asymptomatic DVT and symptomatic DVT as evidenced by an increased requirement for multiple replacements of CVCs when compared to non DVT controls.(5) Of note, the risk for increased requirement for CVC replacement was similar for symptomatic DVT (odds ratio 5.1 95% CI 2.2,11.7) and asymptomatic DVT (odds ratio 5.5 95% CI 1.05,29). These data indicate asymptomatic and symptomatic DVT have comparable risk for CVC loss due to significant venous occlusion. In addition, long term sequelae, such as post thrombotic syndrome has been observed in comparable frequencies after asymptomatic DVT and symptomatic DVT by several studies (6-8)
This article is protected by copyright. All rights reserved.
Accepted Article
In the letter by Jones et al, the bleeding event rate for heparin therapy in children is stated as being up to 56%, however, that bleeding rate was in fact reported from older adult treatment studies. The authors make reference to a pediatric study with unfractionated heparin given at therapeutic doses to critically ill patients, but the bleeding rate was actually 24% in a very high risk population.(9) Pertinent to the discussion here, the dosage for pediatric prophylactic anticoagulation would be considerably lower than for treatment. In terms of the bleeding event rate in primary prophylaxis studies, the best data are from the PROTEKT trial, in which the rate of major bleeding was 1% in the non-anticoagulant/standard of care arm and 0% in the prophylaxis arm using low molecular weight heparin.(10) Of note, use of new oral anticoagulants has the potential for lower risk of bleeding. The optimal way to establish the bleeding event rate and the risk benefit ratio of primary prophylaxis is through randomised controlled clinical trials with standardised outcome definitions for bleeding and DVT.(11)
While we agree that there is a need for prospectively collected long term follow up, we are convinced that the most valid and efficient way to assess both the effect of thromboprophylaxis as well as long-term relevance of symptomatic versus asymptomatic DVT would be interventional randomised controlled trial followed by long-term follow-up. We also agree that there is a growing movement for institutions, and increasing internal and external pressures on hematologists, to develop their own thromboprophylaxis clinical guidelines based on no or little evidence. The urgency around this topic highlights that prevention of DVT in children is an important clinical goal and the development of CVC
related DVT is viewed as suboptimal clinical care. In the absence of good evidence, health care providers are left with adopting unproven practices in the best efforts to manage their patients. Importantly, as these non-evidence based guidelines become standard of care, the opportunity to do any properly designed clinical trials will be lost, as, based on no or little evidence, equipoise on the issue will no longer exist. We argue there is a need for appropriately designed clinical trials as basis for best practice guidelines and any further delay in implementing these trials will only lead to more non-evidence based changes in practice. Finally, we challenge the statement by Jones et al that “‘…Early detection and treatment of thrombosis may well be a safer and more effective option than widespread
This article is protected by copyright. All rights reserved.
Accepted Article
thromboprophylaxis, given the risk benefit ratio of anticoagulation of sick children is also uncertain…’” Waiting for occlusion to occur means the child now requires full-dose anticoagulation over several months, is at risk of acute complications such as loss of venous access, has the potential for non-resolution of the DVT, as well as risk for DVT recurrence and post thrombotic syndrome. This scenario seems to have many disadvantages compared to preventing a DVT a priori, if primary prophylaxis is shown to be efficacious and safe in clinical trials.
Addendum The first draft of the letter was written by C. Male and L. G. Mitchell, with subsequent and final drafts written by all four authors. All authors reviewed and approved the final version.
Conflict of Interest L. G. Mitchell reports personal fees from Boehringer Ingleheim; grants and personal fees from Bristol Myers Squibb, outside the submitted work; and is a member of the Steering Committee for the AESOP trial (Apixaban prEventionS of thrOmbosis in Pediatrics) which is trial assessing primary prophylaxis with anticoagulation for prevention of deep vein thrombosis in children with central venous lines. V. Rodriguez served as co Principal Investigator in a study on Apixaban for the Children's Oncology Group sponsored by Bristol Myers Squib, outside the submitted work S. O'Brien served as the Principal Investigator in a study on DVT prophylaxis in children with leukaemia for the Children's Oncology Group sponsored by for a Bristol Myers, outside the submitted work. C. Male served on steering committees for Bristol-Myers-Squibb and Bayer, outside the submitted work. Reference List (1) Vidal E, Sharathkumar A, Glover J, Faustino EV: Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis. J Thromb Haemost 2014; 12:1096. (2) Jones S, Ignjatovic V, Monagle P, Newall F: Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis: comment. J Thromb Haemost 2014.
This article is protected by copyright. All rights reserved.
Accepted Article
(3) Male C, Kuhle S, Mitchell L: Diagnosis of venous thromboembolism in children. Semin Thromb Hemost 2003; 29:377. (4) Mitchell LG, Andrew M, Hanna K, Abshire T, Halton J, Anderson R, Cherrick I, Desai S, Mahoney D, McCuster P, Wu J, Dahl G, Chait P, de VG, Lee KJ, Mikulis D, Ginsberg J, Way C: A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with L-asparaginase: results of the Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) Study. Cancer 2003; 97:508.
(5) Kulkarni K, Halton J, Spavor M, Israels SJ, Abish S, Yong J, Yasui Y, Mitchell LG: Increased requirement for central venous catheter replacement in paediatric oncology patients with deep venous thrombosis: A multicentre study. Thromb Haemost 2014; 113. (6) Kuhle S, Spavor M, Massicotte P, Halton J, Cherrick I, Dix D, Mahoney D, Bauman M, Desai S, Mitchell LG: Prevalence of post-thrombotic syndrome following asymptomatic thrombosis in survivors of acute lymphoblastic leukemia. J Thromb Haemost 2008; 6:589.
(7) Van Ommen CH, Ottenkamp J, Lam J, Brennickmeier M, Heijmans HS, Buller HR, Peters M: The risk of postthrombotic syndrome in children with congenital heart disease. J Pediatr 2002; 141:582. (8) Polen E, Weintraub M, Stoffer C, Jaffe DH, Burger A, Revel-Vilk S: Post-thrombotic syndrome after central venous catheter removal in childhood cancer survivors: A prospective cohort study. Pediatr Blood Cancer 2014 (9) Kuhle S, Eulmesekian P, Kavanagh B, Massicotte P, Vegh P, Mitchell LG: A clinically significant incidence of bleeding in critically ill children receiving therapeutic doses of unfractionated heparin: a prospective cohort study. Haematologica 2007; 92:244.
(10) Massicotte P, Julian JA, Gent M, Shields K, Marzinotto V, Szechtman B, Chan AK, Andrew M: An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial. Thromb Res 2003; 109:101.
(11) Mitchell LG, Goldenberg NA, Male C, Kenet G, Monagle P, Nowak-Gottl U: Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children. J Thromb Haemost 2011; 9:1856.
This article is protected by copyright. All rights reserved.
