- Email: [email protected]
Evidence-Based Medicine Comes of Age in Pediatric Cardiology
Journal of the American College of Cardiology 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.
News
from the
Vol. 61, No. 25, 2013 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.03.054
NHLBI
Evidence-Based Medicine Comes of Age in Pediatric Cardiology Gail D. Pearson, MD, SCD, Jonathan R. Kaltman, MD, Michael S. Lauer, MD Bethesda, Maryland
Outcomes have improved significantly in pediatric cardiovascular disease in recent decades. The challenge now is to sustain these advances through innovative clinical trials, fundamental molecular investigations, genetics and genomics, and outreach to families, emphasizing the importance of participating in research. We describe several such efforts and provide a vision of the future for pediatric cardiovascular research. (J Am Coll Cardiol 2013;61:2565–7) ª 2013 by the American College of Cardiology Foundation
I
n November 1944, Eileen Saxon went to sleep in a Johns Hopkins hospital operating room a moribund blue toddler, and woke up a pink pioneer in pediatric cardiovascular medicine. The “blue baby” operation to augment pulmonary blood flow in tetralogy of Fallot, the result of a celebrated collaboration among Alfred Blalock, Helen Taussig, and Vivien Thomas, required no clinical trial to confirm the results: the effect size was large and definitely nonrandom. This medical equivalent of a shot heard around the world launched a new therapeutic era for pediatric cardiovascular medicine. Nearly 70 years later, thanks to the continued application of numerous creative and painstakingly developed strategies, survival for infants and children with congenital heart disease (CHD) is the norm rather than the exception. However, the survival rate is leveling off, and many survivors have both cardiac and noncardiac morbidities. Newer interventions have effect sizes considerably smaller than the blue baby operation. Therefore, to build on the excellent progress of the past, adequately powered multicenter clinical studies are required. The transition to systematic evaluation
From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. The content is solely the responsibility of the authors and does not represent the official views of the National Heart, Lung, and Blood Institute or National Institutes of Health. All authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received January 15, 2013; revised manuscript received March 19, 2013, accepted March 27, 2013.
has been slow in pediatric cardiology, in part because of the large number of different malformations. As a result, at the turn of the current century, very few trials had been conducted. This stood in sharp contrast not only to the long history of evidence-based medicine in adult cardiology, but also to the clear therapeutic successes from the Children’s Oncology Groups. In 1998, coincident with the doubling of the budget for the National Institutes of Health (NIH), new government policies encouraged including children in applicable research; between 1998 and 2003, NIH spending on pediatric research increased by >80% (1). In 2001, the National Heart, Lung, and Blood Institute (NHLBI), NIH, launched the Pediatric Heart Network (PHN) (2). The PHN, a sustainable clinical research infrastructure consisting of a data coordinating center, 9 main clinical sites, and more than 25 additional auxiliary sites that help with 1 or more protocols (Fig. 1), focuses primarily on conducting clinical trials. The PHN has completed 3 clinical trials, with 2 more currently underway. The PHN also devotes resources to observational studies and the development of resources to facilitate future trials. The network research structure offers several possible advantages. Because investment is diversified, investigators and the NIH may be more willing to allocate resources to innovative, higher-risk studies, such as the PHN’s comparative effectiveness randomized trial comparing 2 surgical strategies for the initial palliation of infants with single ventricle physiology (3). The PHN infrastructure facilitates strategic
2566
Pearson et al. Evidence-Based Medicine in Pediatric Cardiology
adjustment. On the single occasion when the PHN needed to stop a clinical trial that was not recruiting, B2B = Bench to Bassinet it was easier to do so quickly, Program because there were other “shovel CHD = congenital heart ready” projects ready to begin. disease The network model can also GUID = Global Unique contribute to “learning health care Identifier systems,” not only through genNHLBI = National Heart, erating knowledge from clinical Lung, and Blood Institute trials, but also by enabling other NIH = National Institutes of Health kinds of resources. The PHN developed the Children and CliniPCGC = Pediatric Cardiac Genomics Consortium cal Studies website as a guide for families contemplating inPHN = Pediatric Heart Network volvement in any type of pediatric research (4). The network model has important limitations. The PHN, even with its more than 25 auxiliary sites (Fig. 1), does not include the majority of the programs that care for children with CHD, in contrast to the Children’s Oncology Group, which represents a model that ideally we could emulate. The limited scope could adversely affect the generalizability of PHN findings. Although the program has expanded over time, we cannot predict whether further expansion will be possible. Arguably, the limited scope has also created a “have and have not” division in the pediatric cardiology community; participation in the network is now used to Abbreviations and Acronyms
JACC Vol. 61, No. 25, 2013 June 25, 2013:2565–7
score a program in the US News and World Report rankings. Budgets for individual trials are necessarily limited by the desire to conduct multiple studies in each 5-year grant cycle. The PHN often looks to foundations and drug companies for additional funding and in-kind donations, which although invaluable, generate vulnerability if the funds cannot be made available, especially if this occurs after resources have been invested in developing study protocols. This is not just a theoretical problem; we recently spent a year developing a trial, only to have to abort the project because a drug company changed its mind about supplying the study drug. In 2009, 2 consortia joined the PHN to complete a translational research continuum now known as the Bench to Bassinet (B2B) Program: the Cardiovascular Development Consortium, and the Pediatric Cardiac Genomics Consortium (PCGC) (5). B2B links the dramatic developments in cardiovascular genomics and developmental biology to the clinical studies focused on congenital heart disease, and is one of several ongoing NHLBI experiments in translational research. The overall goal is to understand the causes of and influence the outcome of pediatric cardiovascular disease from the molecular level to humans. This approach is already yielding useful collaborations, such as a recent analysis by a PCGC investigator of DNA from 2 PHN trials that included infants with single ventricle physiology (6). In the current budget climate, a question that arises is how decisions are made to balance funding between investigator-
Figure 1 Location Map This map shows the 9 main clinical sites in North America (maroon), the additional auxiliary sites (blue), the data coordinating center (yellow), and the locations of the Protocol Chair (purple) and National Heart, Lung, and Blood Institute (NHLBI) (green).
Pearson et al. Evidence-Based Medicine in Pediatric Cardiology
JACC Vol. 61, No. 25, 2013 June 25, 2013:2565–7
initiated grants, such as R01s, and large programs like B2B. NHLBI still devotes the majority of its budget to investigator-initiated grants, but as Ioannidis has pointed out (7), it is not clear whether funds are better spent on NIHinitiated programs like the B2B Program or on investigatorinitiated grants. As a result, NHLBI is engaged in a process of results-based accountability (8) and portfolio analysis (9) to provide better data to help us evaluate such important questions. Furthermore, we are carefully considering various approaches to help us determine when, and even whether, it is most appropriate for NHLBI to divert monies away from purely investigator-initiated research. B2B allows us to envision a future where every child with CHD will be identified and diagnosed early, have the nature of the condition described using consistent sophisticated phenotypic ontologies, have DNA banked, be followed longitudinally through federated databases and electronic health records, and be offered the opportunity to participate in therapeutic trials. To begin to meet this challenge, we are borrowing a tool from the autism research community: the Global Unique Identifier (GUID) (10). The GUID is generated based on answers to a few simple questions; 1-way computer hash code preserves confidentiality. The autism research community has used the GUID to track patients between studies and through time (10), resulting in analyses that include larger numbers of patients that do not require the more complicated process of merging datasets. We plan to apply this approach to linking data that currently resides in multiple CHD databases. A potential use of the GUID in CHD could be to seamlessly link genomic data from the PCGC database to neurodevelopmental outcome data from a PHN study or to surgical outcome data from the Society for Thoracic Surgeons’ database. We also envision a future where patients, families, and advocacy communities will be more fully engaged in the research process, helping to set the research agenda and refine the research experience. For example, the National Marfan Foundation partnered with NIH to support and encourage enrollment in the PHN’s Marfan trial (11), which is testing the hypothesis that losartan will prove more effective than atenolol in reducing the rate of aortic root growth. We believe that future progress will require the NIH and investigators to take advantage of emerging technologies (mobile devices, bioinformatics tools, high-throughput genomics) and emerging opportunities (large datasets, integrated and standardized data resources) all working
2567
together with engaged patients and families. Ideally, every child afflicted with CHD will have the opportunity to contribute, safely, to the advancement of knowledge. The evolution of pediatric cardiology research from the blue baby operation to the B2B program has required the dedicated work of investigators, nurses, and study coordinators along with the bravery of patients and families. The result has been significant advances in mortality and quality of life. Our challenge now is to keep faith with Blalock, Taussig, Thomas, and Eileen Saxon, and to keep pushing the field beyond the horizon. Reprints and correspondence: Dr. Gail D. Pearson, Adult and Pediatric Cardiac Research Program, Division of Cardiovascular Sciences, NHLBI/NIH 6701 Rockledge Drive, Room 8132, Bethesda, Maryland 20892. E-mail: [email protected]. REFERENCES
1. Gitterman DP, Greenwood RS, Kocis KC, Mayes BR, McKethan AN. Did a rising tide lift all boats? The NIH budget and pediatric research portfolio. Health Affairs 2004;23:112–24. 2. Mahony L, Sleeper LA, Anderson PA, et al. The Pediatric Heart Network: a primer for the conduct of multicenter studies in children with congenital and acquired heart disease. Pediatr Cardiol 2006;27: 191–8. 3. Ohye RG, Sleeper LA, Mahony L, et al. Comparison of shunt types in the Norwood procedure for single-ventricle lesions. N Engl J Med 2010;362:1980–92. 4. Kuehn BM. Pediatric research gets boost from web. JAMA 2008;300: 2357–8. 5. Kaltman JR, Schramm C, Pearson GD. The National Heart, Lung, and Blood Institute Bench to Bassinet Program: a new paradigm for translational research. J Am Coll Cardiol 2010;55:1262–5. 6. Liang L, Southard AE, Mei H, et al. Enrichment of 16p13.1 copy number variants in infants with single ventricle heart defects. Presented at: American College of Medical Genetics and Genomics Annual Meeting, Charlotte, NC, March 2012. 7. Ioannidis JPA. Fund people not projects. Nature 2011;477:529–30. 8. Lauer MS. Thought exercises on accountability and performance measures at the National Heart, Lung, and Blood Institute (NHLBI): an invited commentary. Circ Res 2011;108:405–9. 9. Galis ZS, Hoots WK, Kiley JP, Lauer MS. On the value of portfolio diversity in heart, lung, and blood research. Circ Res 2012;111:833–6. 10. Johnson SB, Whitney G, McAuliffe M, et al. Using global unique identifiers to link autism collections. J Am Med Inform Assoc 2010;17: 689–95. 11. Lacro RV, Dietz HC, Wruck LM, et al. Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome. Am Heart J 2007;154:624–31. Key Words: congenital heart disease pediatric cardiovascular research.
-
congenital heart surgery
-
News
from the
Vol. 61, No. 25, 2013 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.03.054
NHLBI
Evidence-Based Medicine Comes of Age in Pediatric Cardiology Gail D. Pearson, MD, SCD, Jonathan R. Kaltman, MD, Michael S. Lauer, MD Bethesda, Maryland
Outcomes have improved significantly in pediatric cardiovascular disease in recent decades. The challenge now is to sustain these advances through innovative clinical trials, fundamental molecular investigations, genetics and genomics, and outreach to families, emphasizing the importance of participating in research. We describe several such efforts and provide a vision of the future for pediatric cardiovascular research. (J Am Coll Cardiol 2013;61:2565–7) ª 2013 by the American College of Cardiology Foundation
I
n November 1944, Eileen Saxon went to sleep in a Johns Hopkins hospital operating room a moribund blue toddler, and woke up a pink pioneer in pediatric cardiovascular medicine. The “blue baby” operation to augment pulmonary blood flow in tetralogy of Fallot, the result of a celebrated collaboration among Alfred Blalock, Helen Taussig, and Vivien Thomas, required no clinical trial to confirm the results: the effect size was large and definitely nonrandom. This medical equivalent of a shot heard around the world launched a new therapeutic era for pediatric cardiovascular medicine. Nearly 70 years later, thanks to the continued application of numerous creative and painstakingly developed strategies, survival for infants and children with congenital heart disease (CHD) is the norm rather than the exception. However, the survival rate is leveling off, and many survivors have both cardiac and noncardiac morbidities. Newer interventions have effect sizes considerably smaller than the blue baby operation. Therefore, to build on the excellent progress of the past, adequately powered multicenter clinical studies are required. The transition to systematic evaluation
From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. The content is solely the responsibility of the authors and does not represent the official views of the National Heart, Lung, and Blood Institute or National Institutes of Health. All authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received January 15, 2013; revised manuscript received March 19, 2013, accepted March 27, 2013.
has been slow in pediatric cardiology, in part because of the large number of different malformations. As a result, at the turn of the current century, very few trials had been conducted. This stood in sharp contrast not only to the long history of evidence-based medicine in adult cardiology, but also to the clear therapeutic successes from the Children’s Oncology Groups. In 1998, coincident with the doubling of the budget for the National Institutes of Health (NIH), new government policies encouraged including children in applicable research; between 1998 and 2003, NIH spending on pediatric research increased by >80% (1). In 2001, the National Heart, Lung, and Blood Institute (NHLBI), NIH, launched the Pediatric Heart Network (PHN) (2). The PHN, a sustainable clinical research infrastructure consisting of a data coordinating center, 9 main clinical sites, and more than 25 additional auxiliary sites that help with 1 or more protocols (Fig. 1), focuses primarily on conducting clinical trials. The PHN has completed 3 clinical trials, with 2 more currently underway. The PHN also devotes resources to observational studies and the development of resources to facilitate future trials. The network research structure offers several possible advantages. Because investment is diversified, investigators and the NIH may be more willing to allocate resources to innovative, higher-risk studies, such as the PHN’s comparative effectiveness randomized trial comparing 2 surgical strategies for the initial palliation of infants with single ventricle physiology (3). The PHN infrastructure facilitates strategic
2566
Pearson et al. Evidence-Based Medicine in Pediatric Cardiology
adjustment. On the single occasion when the PHN needed to stop a clinical trial that was not recruiting, B2B = Bench to Bassinet it was easier to do so quickly, Program because there were other “shovel CHD = congenital heart ready” projects ready to begin. disease The network model can also GUID = Global Unique contribute to “learning health care Identifier systems,” not only through genNHLBI = National Heart, erating knowledge from clinical Lung, and Blood Institute trials, but also by enabling other NIH = National Institutes of Health kinds of resources. The PHN developed the Children and CliniPCGC = Pediatric Cardiac Genomics Consortium cal Studies website as a guide for families contemplating inPHN = Pediatric Heart Network volvement in any type of pediatric research (4). The network model has important limitations. The PHN, even with its more than 25 auxiliary sites (Fig. 1), does not include the majority of the programs that care for children with CHD, in contrast to the Children’s Oncology Group, which represents a model that ideally we could emulate. The limited scope could adversely affect the generalizability of PHN findings. Although the program has expanded over time, we cannot predict whether further expansion will be possible. Arguably, the limited scope has also created a “have and have not” division in the pediatric cardiology community; participation in the network is now used to Abbreviations and Acronyms
JACC Vol. 61, No. 25, 2013 June 25, 2013:2565–7
score a program in the US News and World Report rankings. Budgets for individual trials are necessarily limited by the desire to conduct multiple studies in each 5-year grant cycle. The PHN often looks to foundations and drug companies for additional funding and in-kind donations, which although invaluable, generate vulnerability if the funds cannot be made available, especially if this occurs after resources have been invested in developing study protocols. This is not just a theoretical problem; we recently spent a year developing a trial, only to have to abort the project because a drug company changed its mind about supplying the study drug. In 2009, 2 consortia joined the PHN to complete a translational research continuum now known as the Bench to Bassinet (B2B) Program: the Cardiovascular Development Consortium, and the Pediatric Cardiac Genomics Consortium (PCGC) (5). B2B links the dramatic developments in cardiovascular genomics and developmental biology to the clinical studies focused on congenital heart disease, and is one of several ongoing NHLBI experiments in translational research. The overall goal is to understand the causes of and influence the outcome of pediatric cardiovascular disease from the molecular level to humans. This approach is already yielding useful collaborations, such as a recent analysis by a PCGC investigator of DNA from 2 PHN trials that included infants with single ventricle physiology (6). In the current budget climate, a question that arises is how decisions are made to balance funding between investigator-
Figure 1 Location Map This map shows the 9 main clinical sites in North America (maroon), the additional auxiliary sites (blue), the data coordinating center (yellow), and the locations of the Protocol Chair (purple) and National Heart, Lung, and Blood Institute (NHLBI) (green).
Pearson et al. Evidence-Based Medicine in Pediatric Cardiology
JACC Vol. 61, No. 25, 2013 June 25, 2013:2565–7
initiated grants, such as R01s, and large programs like B2B. NHLBI still devotes the majority of its budget to investigator-initiated grants, but as Ioannidis has pointed out (7), it is not clear whether funds are better spent on NIHinitiated programs like the B2B Program or on investigatorinitiated grants. As a result, NHLBI is engaged in a process of results-based accountability (8) and portfolio analysis (9) to provide better data to help us evaluate such important questions. Furthermore, we are carefully considering various approaches to help us determine when, and even whether, it is most appropriate for NHLBI to divert monies away from purely investigator-initiated research. B2B allows us to envision a future where every child with CHD will be identified and diagnosed early, have the nature of the condition described using consistent sophisticated phenotypic ontologies, have DNA banked, be followed longitudinally through federated databases and electronic health records, and be offered the opportunity to participate in therapeutic trials. To begin to meet this challenge, we are borrowing a tool from the autism research community: the Global Unique Identifier (GUID) (10). The GUID is generated based on answers to a few simple questions; 1-way computer hash code preserves confidentiality. The autism research community has used the GUID to track patients between studies and through time (10), resulting in analyses that include larger numbers of patients that do not require the more complicated process of merging datasets. We plan to apply this approach to linking data that currently resides in multiple CHD databases. A potential use of the GUID in CHD could be to seamlessly link genomic data from the PCGC database to neurodevelopmental outcome data from a PHN study or to surgical outcome data from the Society for Thoracic Surgeons’ database. We also envision a future where patients, families, and advocacy communities will be more fully engaged in the research process, helping to set the research agenda and refine the research experience. For example, the National Marfan Foundation partnered with NIH to support and encourage enrollment in the PHN’s Marfan trial (11), which is testing the hypothesis that losartan will prove more effective than atenolol in reducing the rate of aortic root growth. We believe that future progress will require the NIH and investigators to take advantage of emerging technologies (mobile devices, bioinformatics tools, high-throughput genomics) and emerging opportunities (large datasets, integrated and standardized data resources) all working
2567
together with engaged patients and families. Ideally, every child afflicted with CHD will have the opportunity to contribute, safely, to the advancement of knowledge. The evolution of pediatric cardiology research from the blue baby operation to the B2B program has required the dedicated work of investigators, nurses, and study coordinators along with the bravery of patients and families. The result has been significant advances in mortality and quality of life. Our challenge now is to keep faith with Blalock, Taussig, Thomas, and Eileen Saxon, and to keep pushing the field beyond the horizon. Reprints and correspondence: Dr. Gail D. Pearson, Adult and Pediatric Cardiac Research Program, Division of Cardiovascular Sciences, NHLBI/NIH 6701 Rockledge Drive, Room 8132, Bethesda, Maryland 20892. E-mail: [email protected]. REFERENCES
1. Gitterman DP, Greenwood RS, Kocis KC, Mayes BR, McKethan AN. Did a rising tide lift all boats? The NIH budget and pediatric research portfolio. Health Affairs 2004;23:112–24. 2. Mahony L, Sleeper LA, Anderson PA, et al. The Pediatric Heart Network: a primer for the conduct of multicenter studies in children with congenital and acquired heart disease. Pediatr Cardiol 2006;27: 191–8. 3. Ohye RG, Sleeper LA, Mahony L, et al. Comparison of shunt types in the Norwood procedure for single-ventricle lesions. N Engl J Med 2010;362:1980–92. 4. Kuehn BM. Pediatric research gets boost from web. JAMA 2008;300: 2357–8. 5. Kaltman JR, Schramm C, Pearson GD. The National Heart, Lung, and Blood Institute Bench to Bassinet Program: a new paradigm for translational research. J Am Coll Cardiol 2010;55:1262–5. 6. Liang L, Southard AE, Mei H, et al. Enrichment of 16p13.1 copy number variants in infants with single ventricle heart defects. Presented at: American College of Medical Genetics and Genomics Annual Meeting, Charlotte, NC, March 2012. 7. Ioannidis JPA. Fund people not projects. Nature 2011;477:529–30. 8. Lauer MS. Thought exercises on accountability and performance measures at the National Heart, Lung, and Blood Institute (NHLBI): an invited commentary. Circ Res 2011;108:405–9. 9. Galis ZS, Hoots WK, Kiley JP, Lauer MS. On the value of portfolio diversity in heart, lung, and blood research. Circ Res 2012;111:833–6. 10. Johnson SB, Whitney G, McAuliffe M, et al. Using global unique identifiers to link autism collections. J Am Med Inform Assoc 2010;17: 689–95. 11. Lacro RV, Dietz HC, Wruck LM, et al. Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome. Am Heart J 2007;154:624–31. Key Words: congenital heart disease pediatric cardiovascular research.
-
congenital heart surgery
-