The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group meeting on June 14-15, 2012 in Bethesda, MD to explore the issues relevant to thrombosis (prevention, detection/surveillance, treatment) in pediatric cardiology and adult congenital heart disease patients. The goals of the Working Group were to:
- Review in detail the current state of knowledge about thrombosis and incorporate additional knowledge derived from studies and guidelines relevant to adult populations.
- Identify gaps in the knowledge base and prioritize opportunities for using basic and clinical research to close these gaps.
- Develop strategies and resources for knowledge translation and implementation science to improve the overall care of these populations.
The working group consisted of experts in pediatric cardiology, hematology, and neurology, adult cardiology and hematology, basic science of coagulation, imaging, and dissemination and implementation of guidelines along with representatives from the pharmaceutical industry and the Food and Drug Administration. The Working Group's charge was responsive to the NHLBI Strategic Plan Goals 1, 2, and 3.
Thrombosis, its sequelae, and complications related to management are increasingly recognized as important contributors to morbidity and mortality among children with congenital and acquired heart disease and adults with congenital heart disease. The prevalence and relevance of thrombosis in these populations are informed by unique factors, such as developmental and acquired abnormalities in thrombosis and fibrinolysis (e.g., physiologically low levels of anticoagulants, including antithrombin and protein C, in neonates and patients with functional single ventricle), and the presence of specific high-risk conditions (e.g., Kawasaki disease, perioperative state in patients undergoing open heart surgery, prosthetic heart valves). The pathophysiology, incidence, associated risk factors, clinical relevance, and optimal strategies for prevention, detection/surveillance, and management of thrombosis in these populations are poorly understood.
The insufficient evidence base in the field has been highlighted by recent clinical recommendations from the American College of Chest Physicians [Antithrombotic Therapy in Neonates and Children; Chest 2012;141;e737S-e801S] and the AHA Council on Cardiovascular Disease in the Young [Prevention and Treatment of Thrombosis in Children and Adults with Congenital Heart Disease and in Children with Acquired Heart Disease; under review]. These guidelines were characterized by absence of high-grade levels of evidence on which to base recommendations.
The introduction of newer anticoagulation therapies, such as anti-platelet agents and direct thrombin and Xa inhibitors, their success in adult patients, and industry's interest in developing pediatric trials combine to offer the opportunity to improve our current understanding of therapeutics, identify areas requiring further study, and develop a coordinated plan for testing these newer agents. Multidisciplinary and cross-agency coordination is critical when caring for a rare disease population; otherwise, isolated research efforts will pursue (ultimately unsuccessfully) a limited patient cohort.
The Working Group discussed the challenges and knowledge gaps in the area of thrombosis management in pediatric cardiology and adult congenital heart disease. To improve the knowledge base in this field, the Working Group made several recommendations.
- Multidisciplinary approach. Planning groups for future scientific statements and conceptualization of clinical studies and trials should embrace a multidisciplinary approach, including experts from cardiology, hematology, neurology, imaging, and basic science. Inclusion of dissemination and implementation experts in the planning phase of these activities may increase the likelihood for widespread acceptance and adoption of recommendations or study results.
- Clinical populations/study subjects. The Working Group identified several clinical populations that require more intensive study with regard to thrombosis identification and management. These populations include patients with Kawasaki disease, patients with single ventricles, patients with prosthetic valves (especially young children), patients with ventricular assist devices, and patients undergoing cardiopulmonary bypass. Identifying the appropriate comparison population was also noted to be a critical issue.
- Endpoints. Hard clinical endpoints, such as death or stroke, fortunately are rare in this patient population. Therefore, the Working Group recommended development and validation of clinically relevant endpoints. The Working Group encouraged the use of net clinical benefit as a concept for endpoint development. Net clinical benefit incorporates both benefits and risks into endpoint determination. Patient preferences and quality of life should also be considered. Clinically relevant imaging and blood-based biomarkers should be further investigated as potential surrogate endpoints. The challenges of evaluating short-versus long-term outcomes were also discussed.
- Study design. Large-scale randomized, placebo-blind, Phase III trials are likely to be an inefficient study design in this population with rare events. Smaller trials with novel designs, such as cross-over or adaptive, may be more feasible and provide higher statistical power. Important epidemiologic and risk factor data can be determined from observational studies, registries, and case-control studies. Trials nested within a registry, as well as ancillary mechanistic studies embedded within clinical trials, were discussed. Leveraging existing resources such as the Cardiovascular Research Network, the National Cardiovascular Data Registry, the DBDR-based trial planning grants for rare hemostatic diseases, as well as the NHLBI pilot trials and ancillary study mechanisms, was also discussed.
- Industry-sponsored studies. Pharmaceutical companies are actively developing novel anticoagulation and anti-platelet agents and will need to evaluate these agents in pediatric and congenital heart patients. The Working Group recommended that companies, in partnership with academic centers and the FDA, should, where possible, coordinate their activities in this small patient population. The Working Group also recommended that all stakeholders should facilitate the conduct of pharmacokinetic/pharmacodynamic studies of novel agents in pediatric patients. Completion of such studies is needed before these agents can be evaluated in Phase II/III trials in this population. Finally, the Working Group recommended that both industry -sponsored and investigator-initiated trials should be leveraged with ancillary imaging and mechanistic studies to maximize their value.
The Working Group committee will develop a report of the meeting for publication in an appropriate professional journal.
Division of Cardiovascular Sciences
Division of Blood Diseases and Resources
Jonathan Kaltman, MD
Working Group Members
- Brian McCrindle, MD, MPH, Hospital for Sick Children
- Jennifer Li, MD, Duke University
- Christopher Almond, MD, Boston Children's Hospital
- Leonardo Brandao, MD, Hospital for Sick Children
- Anthony Chan, MD, McMaster University
- Nakela Cook, MD, MPH, National Heart, Lung, and Blood Institute
- Charles Esmon, PhD, Oklahoma Medical Research Foundation
- Rebecca Ichord, MD, Children's Hospital of Philadelphia
- Rajesh Krishnamurthy, MD, Texas Children's Hospital
- Kenneth Mahaffey, MD, Duke University
- Marilyn Manco-Johnson, MD, University of Colorado
- Patti Massicotte, MD, University of Alberta, Edmonton
- Jane W. Newburger, MD, MPH, Boston Children's Hospital
- Thomas Ortel, MD, Duke University
- Ronald Portman, MD, Bristol Myers Squibb
- Martin Rose, MD, Food and Drug Administration
- John Strony, MD, Merck
- James Tweddell, MD, Children's Hospital of Wisconsin
- Nicole Verdun, MD, Children's National Medical Center
- Therese Giglia, MD, Children's Hospital of Philadelphia
- Alan Michelson, MD, Boston Children's Hospital
- Paul Monagle, MD, The Royal Children's Hospital
- Gail Pearson, MD, ScD
- Donna DiMichele, MD
- Ellen Rosenberg, RN
Last Updated: September 2012