NEWS & VIEWS THROMBOSIS
Congenital heart disease and thrombosis: what do we know? Paul Monagle
A scientific statement on the prevention and treatment of thrombosis in children with congenital heart disease has been published by Giglia et al. on behalf of the AHA. This paper adds substantially to the current literature, and yet highlights the major limitations in our current understanding and knowledge in this field. Monagle, P. Nat. Rev. Cardiol. 11, 132–134 (2014); published online 7 January 2014; doi:10.1038/nrcardio.2013.217
A scientific statement on the prevention and treatment of thrombosis in children with congenital heart disease has been published in Circulation by Giglia et al. on behalf of the AHA.1 In addition, in 2012, the American College of Chest Physicians (ACCP) published evidence-based guidelines on antithrombotic therapy in children.2 So, do we now have two complementary or contradictory sets of guidelines, and how far have these combined efforts really advanced the field? The subject of thrombosis in children, especially those with cardiac disease, is undoubtedly very topical. So much so that, in June 2012, the US National Heart, Lung, and Blood Institute convened a working party to review the current state of knowledge in the field, prioritize opportunities for basic and clinical research, and develop strategies and resources for knowledge translation and implementation.3 That this meeting was required is not surprising. The major advances in surgical and medical management of children with congenital heart disease over the past few decades have been breathtaking. Considering that Fontan and Baudet first described the definitive palliative procedure for tricuspid atresia in 1971,4 current estimates from the Murdoch Childrens Research Institute Fontan Registry, which is the first of its kind in the world, that there are >1,000 long-term survivors of the Fontan pro cedure in Australia alone are amazing.5 On a global scale, adult survivors of congenital heart disease must now form a very large population. Many clinicians will remember hypoplastic left heart syndrome as being
a terminal condition during infancy, and yet now the success of the Norwood procedure is reported to be >80%.6 The ability to sustain neonates on ventricular assist devices for prolonged periods of time is a further revolution in the approach to severe congenital heart disease in infancy. However, with these dramatic improvements in survival come secondary complications, of which thromboembolism is perhaps the most devastating. Labelled as the ‘new epidemic of tertiary paediatrics’, 7 the data suggest a threefold to 10‑fold increase in the frequency of venous thromboembolism diagnosis in children hospitalized over the past 15 years.8 The mortality (2.2% directly attributable to venous thromboembolism) and morbidity (recurrence rates of 4.0–21.3% and an overall rate of post-thrombotic syndrome (Figure 1) of 26%) of thrombosis in children are considerable.8 Embolic stroke is all too common, and the successful treatment of major cardiac defects never seems sufficient when a child has been rendered hemiparetic with residual seizures after a postsurgical stroke. One could argue that very little progress has been made in our approach to the treatment of thrombosis in children in the two decades since Maureen Andrew and colleagues first described the epidemiology of thrombosis in children.9 When the ACCP paediatric guidelines were first published in 1995, the authors made 100 recommendations but, unfortunately, the majority are still at the
NATURE REVIEWS | CARDIOLOGY
grade 2C level of evidence and are not uniformly used.8 A grade 2C level of evidence invariably means that the data supporting the recommendation are drawn from observational studies, and the methodology for comparing and prioritizing observational studies has important limitations. Most of the major randomized controlled trials in paediatric thrombosis treatment have been closed short of their recruitment targets.8,10 Therefore, the fact that some differences exist between the AHA scientific statement 1 and the ACCP guidelines2 is not surprising. A major variable in determining anti thrombotic guidelines for children is how much emphasis to put on poor-quality studies performed in children, versus highquality studies of the same condition in adults. Much of the data for paediatric recommendations are still extrapolated from adult data, but modified according to the differences between children and adults in physiology (such as developmental haemo stasis, differences in blood flow, unique paediatric circumstances, and perceptions of altered bleeding risks, for example owing to prematurity), in the pathophysiol ogy
Figure 1 | Chronic venous insufficiency associated with thomboembolism (postthrombotic syndrome) in a 13-year-old, female, long-term survivor of Fontan surgery. The patient had cardiac catheterization via her femoral vein 10 years previously, which was thought to have been uneventful.
VOLUME 11 | MARCH 2014 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS of the disease, and in the known pharma cology of drugs (such as mechanisms of action and effects). Therefore, the weighting of the adult data versus these paediatric differences is very much a matter of consensus. Furthermore, given that many of these factors change dramatically with age from neonates to older children, each age group might require different recommendations. These deliberations will, in part, depend on how much influence is placed on the concept of developmental haemostasis and its implications for the natural history of thrombosis, and the use of antithrombotic therapy in children. I would contend that, at this time, we have very limited understanding of the normal functioning of the coagulation system in infants and children, let alone how this constantly evolving process interacts with the whole range of available antithrombotic agents.
‘‘
…the pathophysiology and natural history of most thrombotic diseases in children remain uncertain…
’’
In the absence of definitive, high-quality evidence, expert opinion comes into play. Expert opinion is heavily biased by an individual’s experience, and is often influenced by local (geographical) preferences. The way in which clinicians from different countries approach clinical decisions for which little evidence exists differs markedly, because varying degrees of emphasis are placed on different elements of the available evidence. For example, in many situations we see a North American approach and a European approach, with experts from each continent arguing strongly for their rationale, even though these strategies are based on the same literature. A classic example is the difference in the approach to anticoagulation during pregnancy between continents. In part, differences might also be driven by marked variability in costs between and within countries. A treatment or process that is easily accessible in some centres might be logistically very difficult in others. These differences in core services probably vary much more in paediatric than in adult settings, purely because of the smaller patient numbers involved and the inability to support a wide range
MARCH 2014 | VOLUME 11
of staff with complementary skills as often occurs within adult treatment centres. The potential to utilize interventions based on interventional radiology or vascular surgery, for example, varies enormously depending on access. Similarly, many centres vary in terms of coagulation lab oratory support, for example, availability of assays for activated partial thromboplastin time versus anti-factor Xa. We must consider that the true risk–benefit ratio of any treatment can, therefore, vary considerably from centre to centre, and from publication to publication. These differences do not take into account the politics at individual centres, such as which specialists are caring for patients at various times—cardiologists, intensive-care physicians, neonatologists, general pa ediatricians, haematologists, or oncologists. In this context, an important difference between the AHA 1 and ACCP 2 guidelines is that the AHA panel is exclusively North American, whereas the ACCP group included members from many continents. In addition, the chair of each ACCP panel was a methodologist who was not involved in the content; an attempt to reduce the bias of favouring familiarity over evidence, whereas the AHA panel was made up entirely of content experts. That is not to say that either perspective is correct and the other is not, just that differences in guidelines are understandable in the context of author groups, weighting of adult versus paediatric data, cost drivers, models of care, availability of services, and local beliefs. In summary, whether discrepancies exist between the AHA1 and ACCP2 guidelines is irrelevant. The clear message from both papers is that the international paediatric community needs to make a concerted effort to increase the levels of evidence on which any future recommendations are made. The paper by Giglia et al. is comprehensive and useful, describing the current understanding of epidemiology, diagnosis, and pathophysiology of thrombosis in children with congenital heart disease, as well as therapy for these patients.1 What is clear from the AHA guidelines,1 and previous literature, is that the pathophysiology and natural history of most thrombotic diseases in children remain uncertain and diagnostic strategies unproven. Urgent research is required in these areas. Until we understand
the natural history of a disease, how can we understand the risk–benefit ratio of therapy? Lack of diagnostic certainty makes treatment studies difficult to compare. Therefore, considerable effort is needed to improve our understanding of the sensitivity and specificity of various diagnostic strategies, and to reach an agreement on diagnostic principles. We do need more treatment trials, of varying designs, to improve the evidence for current and new antithrombotic agents in children. However, as a first step, we have to ensure diagnostic consistency between studies before treatment outcomes can be compared. Department of Clinical Haematology, Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Flemington Road Parkville, VIC 3052, Australia. [email protected] Competing interests The author declares no competing interests. 1.
Giglia, T. M. et al. Prevention and treatment of thrombosis in pediatric and congenital heart disease: a scientific statement from the American Heart Association. Circulation 128, 2622–2703 (2013). 2. Monagle, P. et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141, e737S–e801S (2012). 3. National Heart, Lung, and Blood Institute. Working Group/Workshop Executive Summary. Thrombosis in Pediatric Cardiology and Adult Congenital Heart Disease [online], http:// www.nhlbi.nih.gov/meetings/workshops/ thrombosis.htm (2012). 4. Fontan, F. & Baudet, E. Surgical repair of tricuspid atresia. Thorax 26, 240–248 (1971). 5. Murdoch Childrens Research Institute. Fontan Registry [online], http://www.fontanregistry.com (2013). 6. Sistino, J. J. & Bonilha, H. S. Improvements in survival and neurodevelopmental outcomes in surgical treatment of hypoplastic left heart syndrome: a meta-analytic review. J. Extra Corpor. Technol. 44, 216–223 (2012). 7. Monagle, P. Anticoagulation in the young. Heart 90, 808–812 (2004). 8. Chan, A. K. & Monagle, P. Updates in thrombosis in pediatrics: where are we after 20 years? Hematology Am. Soc. Hematol. Educ. Program 2012, 439–443 (2012). 9. Andrew, M. et al. Venous thromboembolic complications (VTE) in children: first analysis of the Canadian Registry of VTE. Blood 83, 1251–1257 (1994). 10. Monagle, P. et al. A multicenter, randomized trial comparing heparin/warfarin and acetylsalicylic acid as primary thromboprophylaxis for 2 years after the Fontan procedure in children. J. Am. Coll. Cardiol. 58, 645–651 (2011).
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
Congenital heart disease and thrombosis: what do we know? Paul Monagle
A scientific statement on the prevention and treatment of thrombosis in children with congenital heart disease has been published by Giglia et al. on behalf of the AHA. This paper adds substantially to the current literature, and yet highlights the major limitations in our current understanding and knowledge in this field. Monagle, P. Nat. Rev. Cardiol. 11, 132–134 (2014); published online 7 January 2014; doi:10.1038/nrcardio.2013.217
A scientific statement on the prevention and treatment of thrombosis in children with congenital heart disease has been published in Circulation by Giglia et al. on behalf of the AHA.1 In addition, in 2012, the American College of Chest Physicians (ACCP) published evidence-based guidelines on antithrombotic therapy in children.2 So, do we now have two complementary or contradictory sets of guidelines, and how far have these combined efforts really advanced the field? The subject of thrombosis in children, especially those with cardiac disease, is undoubtedly very topical. So much so that, in June 2012, the US National Heart, Lung, and Blood Institute convened a working party to review the current state of knowledge in the field, prioritize opportunities for basic and clinical research, and develop strategies and resources for knowledge translation and implementation.3 That this meeting was required is not surprising. The major advances in surgical and medical management of children with congenital heart disease over the past few decades have been breathtaking. Considering that Fontan and Baudet first described the definitive palliative procedure for tricuspid atresia in 1971,4 current estimates from the Murdoch Childrens Research Institute Fontan Registry, which is the first of its kind in the world, that there are >1,000 long-term survivors of the Fontan pro cedure in Australia alone are amazing.5 On a global scale, adult survivors of congenital heart disease must now form a very large population. Many clinicians will remember hypoplastic left heart syndrome as being
a terminal condition during infancy, and yet now the success of the Norwood procedure is reported to be >80%.6 The ability to sustain neonates on ventricular assist devices for prolonged periods of time is a further revolution in the approach to severe congenital heart disease in infancy. However, with these dramatic improvements in survival come secondary complications, of which thromboembolism is perhaps the most devastating. Labelled as the ‘new epidemic of tertiary paediatrics’, 7 the data suggest a threefold to 10‑fold increase in the frequency of venous thromboembolism diagnosis in children hospitalized over the past 15 years.8 The mortality (2.2% directly attributable to venous thromboembolism) and morbidity (recurrence rates of 4.0–21.3% and an overall rate of post-thrombotic syndrome (Figure 1) of 26%) of thrombosis in children are considerable.8 Embolic stroke is all too common, and the successful treatment of major cardiac defects never seems sufficient when a child has been rendered hemiparetic with residual seizures after a postsurgical stroke. One could argue that very little progress has been made in our approach to the treatment of thrombosis in children in the two decades since Maureen Andrew and colleagues first described the epidemiology of thrombosis in children.9 When the ACCP paediatric guidelines were first published in 1995, the authors made 100 recommendations but, unfortunately, the majority are still at the
NATURE REVIEWS | CARDIOLOGY
grade 2C level of evidence and are not uniformly used.8 A grade 2C level of evidence invariably means that the data supporting the recommendation are drawn from observational studies, and the methodology for comparing and prioritizing observational studies has important limitations. Most of the major randomized controlled trials in paediatric thrombosis treatment have been closed short of their recruitment targets.8,10 Therefore, the fact that some differences exist between the AHA scientific statement 1 and the ACCP guidelines2 is not surprising. A major variable in determining anti thrombotic guidelines for children is how much emphasis to put on poor-quality studies performed in children, versus highquality studies of the same condition in adults. Much of the data for paediatric recommendations are still extrapolated from adult data, but modified according to the differences between children and adults in physiology (such as developmental haemo stasis, differences in blood flow, unique paediatric circumstances, and perceptions of altered bleeding risks, for example owing to prematurity), in the pathophysiol ogy
Figure 1 | Chronic venous insufficiency associated with thomboembolism (postthrombotic syndrome) in a 13-year-old, female, long-term survivor of Fontan surgery. The patient had cardiac catheterization via her femoral vein 10 years previously, which was thought to have been uneventful.
VOLUME 11 | MARCH 2014 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS of the disease, and in the known pharma cology of drugs (such as mechanisms of action and effects). Therefore, the weighting of the adult data versus these paediatric differences is very much a matter of consensus. Furthermore, given that many of these factors change dramatically with age from neonates to older children, each age group might require different recommendations. These deliberations will, in part, depend on how much influence is placed on the concept of developmental haemostasis and its implications for the natural history of thrombosis, and the use of antithrombotic therapy in children. I would contend that, at this time, we have very limited understanding of the normal functioning of the coagulation system in infants and children, let alone how this constantly evolving process interacts with the whole range of available antithrombotic agents.
‘‘
…the pathophysiology and natural history of most thrombotic diseases in children remain uncertain…
’’
In the absence of definitive, high-quality evidence, expert opinion comes into play. Expert opinion is heavily biased by an individual’s experience, and is often influenced by local (geographical) preferences. The way in which clinicians from different countries approach clinical decisions for which little evidence exists differs markedly, because varying degrees of emphasis are placed on different elements of the available evidence. For example, in many situations we see a North American approach and a European approach, with experts from each continent arguing strongly for their rationale, even though these strategies are based on the same literature. A classic example is the difference in the approach to anticoagulation during pregnancy between continents. In part, differences might also be driven by marked variability in costs between and within countries. A treatment or process that is easily accessible in some centres might be logistically very difficult in others. These differences in core services probably vary much more in paediatric than in adult settings, purely because of the smaller patient numbers involved and the inability to support a wide range
MARCH 2014 | VOLUME 11
of staff with complementary skills as often occurs within adult treatment centres. The potential to utilize interventions based on interventional radiology or vascular surgery, for example, varies enormously depending on access. Similarly, many centres vary in terms of coagulation lab oratory support, for example, availability of assays for activated partial thromboplastin time versus anti-factor Xa. We must consider that the true risk–benefit ratio of any treatment can, therefore, vary considerably from centre to centre, and from publication to publication. These differences do not take into account the politics at individual centres, such as which specialists are caring for patients at various times—cardiologists, intensive-care physicians, neonatologists, general pa ediatricians, haematologists, or oncologists. In this context, an important difference between the AHA 1 and ACCP 2 guidelines is that the AHA panel is exclusively North American, whereas the ACCP group included members from many continents. In addition, the chair of each ACCP panel was a methodologist who was not involved in the content; an attempt to reduce the bias of favouring familiarity over evidence, whereas the AHA panel was made up entirely of content experts. That is not to say that either perspective is correct and the other is not, just that differences in guidelines are understandable in the context of author groups, weighting of adult versus paediatric data, cost drivers, models of care, availability of services, and local beliefs. In summary, whether discrepancies exist between the AHA1 and ACCP2 guidelines is irrelevant. The clear message from both papers is that the international paediatric community needs to make a concerted effort to increase the levels of evidence on which any future recommendations are made. The paper by Giglia et al. is comprehensive and useful, describing the current understanding of epidemiology, diagnosis, and pathophysiology of thrombosis in children with congenital heart disease, as well as therapy for these patients.1 What is clear from the AHA guidelines,1 and previous literature, is that the pathophysiology and natural history of most thrombotic diseases in children remain uncertain and diagnostic strategies unproven. Urgent research is required in these areas. Until we understand
the natural history of a disease, how can we understand the risk–benefit ratio of therapy? Lack of diagnostic certainty makes treatment studies difficult to compare. Therefore, considerable effort is needed to improve our understanding of the sensitivity and specificity of various diagnostic strategies, and to reach an agreement on diagnostic principles. We do need more treatment trials, of varying designs, to improve the evidence for current and new antithrombotic agents in children. However, as a first step, we have to ensure diagnostic consistency between studies before treatment outcomes can be compared. Department of Clinical Haematology, Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Flemington Road Parkville, VIC 3052, Australia. [email protected] Competing interests The author declares no competing interests. 1.
Giglia, T. M. et al. Prevention and treatment of thrombosis in pediatric and congenital heart disease: a scientific statement from the American Heart Association. Circulation 128, 2622–2703 (2013). 2. Monagle, P. et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141, e737S–e801S (2012). 3. National Heart, Lung, and Blood Institute. Working Group/Workshop Executive Summary. Thrombosis in Pediatric Cardiology and Adult Congenital Heart Disease [online], http:// www.nhlbi.nih.gov/meetings/workshops/ thrombosis.htm (2012). 4. Fontan, F. & Baudet, E. Surgical repair of tricuspid atresia. Thorax 26, 240–248 (1971). 5. Murdoch Childrens Research Institute. Fontan Registry [online], http://www.fontanregistry.com (2013). 6. Sistino, J. J. & Bonilha, H. S. Improvements in survival and neurodevelopmental outcomes in surgical treatment of hypoplastic left heart syndrome: a meta-analytic review. J. Extra Corpor. Technol. 44, 216–223 (2012). 7. Monagle, P. Anticoagulation in the young. Heart 90, 808–812 (2004). 8. Chan, A. K. & Monagle, P. Updates in thrombosis in pediatrics: where are we after 20 years? Hematology Am. Soc. Hematol. Educ. Program 2012, 439–443 (2012). 9. Andrew, M. et al. Venous thromboembolic complications (VTE) in children: first analysis of the Canadian Registry of VTE. Blood 83, 1251–1257 (1994). 10. Monagle, P. et al. A multicenter, randomized trial comparing heparin/warfarin and acetylsalicylic acid as primary thromboprophylaxis for 2 years after the Fontan procedure in children. J. Am. Coll. Cardiol. 58, 645–651 (2011).
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
