Pediatric Interventional Cardiology: Innovations Transitioned to Standard of Care

In this issue of Circulation, Feltes et al.[1] summarize the American Heart Association (AHA) recommendations on indications for cardiac catheterization and intervention in pediatric cardiac disease, endorsed by the American Academy of Pediatrics and Society for Cardiovascular Angiography and Intervention. This expanded and excellent update reflecting current practice standards was indeed much overdue, as the field has evolved significantly since the previous AHA statement on this subject in 1998.[2]

Evolution of the field since prior AHA recommendations in 1998

Over the past 12 years, there have been major technological achievements as well as advances in noninvasive testing, such that the indications and use of catheter procedures in pediatric cardiology are very different today compared with what they were then. Several targeted, condition-specific therapies have been developed, progressed through regulatory pathways to reach Food and Drug Administration (FDA) approval, and became standard of care. Such is the case for percutaneous device closure of atrial septal defects.[3-5] muscular ventricular septal defects,[6] and patent ductus arteriosus.[7] With further technological advances, endovascular procedures have expanded use in an increased number of conditions.[8,9] Furthermore, lesions previously considered resistant to interventional therapies can now be managed with high success, such as peripheral pulmonary artery stenosis, obstructive surgical conduits, and acute postoperative stenosis.[8] The introduction of the hybrid approach[10,11] helped to overcome the limitations inherent to percutaneous access, expanding the application of endovascular therapies as adjunct to surgical interventions to improve patient outcomes and minimize invasiveness. Other novel technologies, which were in 1998 considered futuristic dreams, have actually come true to emerge as alternative successful therapies.[12] This is the case for percutaneous pulmonary valve implantation,[12] which is now included in the new indications statement.[1]

Except for a few applications,[3-7] most progress in the field did not result from specific regulatory, industrial, or federal support for pediatric interventional cardiology. Perhaps this was because of a lack of financial incentives to develop novel techniques designed specifically for the relatively small and underserved population of children with congenital heart disease. Despite this, the pediatric interventional cardiology community has continued to develop less invasive solutions to congenital heart defects to minimize the need for open heart surgery and optimize overall outcomes. The vast majority of procedures referred to in this statement[1] result from the innovative adaptation by visionary and skilled practitioners of tools and techniques designed for other indications, aiming to find solutions to pediatric cardiac conditions for which options were unsatisfactory or unnecessarily invasive. For most such interventions, these efforts lead to very acceptable outcomes and low complication rates as compared with the alternative of surgery or no intervention.[8] As the use of novel techniques expanded to become accepted management options for patients with congenital heart disease throughout the world, they extended beyond the pediatric population, such as for the management of structural heart conditions in adults.[13]

Therefore, it is not surprising that most recommendations in the current statement[1] (including those Class I) refer to off-label use of devices approved for other typically adult coronary, peripheral vascular, or noncardiovascular adult indications.[9] Out of 126 recommendations,[1] 56% are based on level of evidence C (consensus opinion), 42% are based on level of evidence B, and less than 2% were based on level of evidence A.

Challenges inherent to the pediatric cardiac patient population The small percentage of recommendations based on level of evidence A[1] reflects the paucity of randomized clinical trials in pediatric cardiology, thought to have been related to multiple factors, including the heterogeneity of pediatric cardiac conditions and the relatively small patient population affected.[14] The expense of multicenter clinical trials in pediatrics with reasonably long follow-up must be balanced against a limited market potential following approval. There appears to have been a disparity in the speed by which novel off-label interventions emerge and become standard of care in this field relative to that of regulatory standards.

Furthermore, the pediatric population poses further challenges to both regulatory agencies as well as industry. In addition to significant technical problems to address, randomized controlled trials are difficult to design in pediatric populations due to ethical and practical concerns of exposing children to risks that may be considered excessive. Poor enrollment in randomized studies is common if the device being tested is thought to be a less invasive and perceived as a likely safer option than the surgical alternative. Enrollment can also be very limited if the device studied, or a very similar version, is commercially available off-label outside of the study protocol, which is not an uncommon occurrence in the field.

Regulatory and legislative changes

Despite the importance and timeliness of the new AHA statement,[1] significant changes have recently occurred from a regulatory perspective that are likely to impact the field further in the near future. Over the past 10 years, there has been an increased awareness by the FDA of the special problems related to drug and device development for children. It is a concern that there are relatively few examples of cardiac devices designed, tested, and approved in the United States specifically for treatment of cardiovascular disease in children. These include[9] atrial septostomy balloons, pulmonary valvuloplasty balloons, devices for closure of secundum atrial septal defects, muscular ventricular septal defect, and patent ductus arteriosus, as well as the most recently approved Melody percutaneous pulmonary valve as a humanitarian device.[12] In contrast, all other procedures referred to in the new statement involve off-label use of devices.[9] Almost all angioplasty balloons are approved for either peripheral vascular, dialysis fistulas or coronary artery interventions in adults, but not for pediatric cardiac applications. Endovascular stents have been approved for either biliary, coronary, or bronchial indications as well as rare peripheral vascular applications. Embolization coils are approved only for arteriovenous fistulae, but are commonly used off-label for closure of aortopulmonary or venous collaterals, or small patent ducts. Regrettably, in a pediatric cardiac catheterization laboratory stent implantation is never on-label. Common pediatric uses include pulmonary artery stenosis, conduit obstruction, systemic venous stenosis and coarctation of the aorta.[1,8,9] Similarly, coronary artery stents are used off-label to restore patency of obstructed small infant shunts, maintain patency of restrictive patent ductus, and rare patients with pulmonary vein stenosis as a bridge to transplantation.[1,8] Cutting balloons are always used off-label to treat resistant pulmonary artery stenosis, creation of an atrial septal defects, or Fontan fenestrations. And the list continues on and on.[10]

It is recognized that in the United States, off-label use of an approved medical device by a physician falls within the bounds of acceptable standard of care. Nevertheless, because this is not the exception in pediatric cardiology but rather the rule, it has raised concern. The need for design and testing of medical devices explicitly intended for pediatric conditions has been recognized by the U.S. Department of Health and Human Services (DHHS) and the FDA. In a 2004 report to Congress, the DHHS and FDA stated that "it is clear that further study is warranted to evaluate the scope of the unmet needs" in reference to pediatric medical devices.[15,16] They recommended that a comprehensive assessment for the development of pediatric-specific devices be performed. The U.S. Congress responded in 2007 with the passage of Title III of the FDA Amendments Act, called the Pediatric Medical Device Safety and Improvement Act.[16] This legislation, among other things, recognized the need for improving postmarket safety monitoring of devices utilized in children and encouraged creation of nonprofit consortia to stimulate innovation in the development of medical devices for children. This law represents a major accomplishment as it was the first ever piece of legislation passed exclusively for pediatric medical devices. It allowed increased FDA authority for tracking of pediatric device approvals. As consequence, the FDA can now require studies longer than 36 months, if necessary, to assess the safety and effectiveness of devices used in growing children. In addition, there was a new incentive for device development secondary to the removal of the humanitarian device exemption profit cap for pediatric devices. It is generally expected that this important legislation will help foster a new era in the development of cardiac devices applicable to children. Whether these changes will stimulate or dissuade financial support for novel technology with use in children remains to be seen.

New direction

Exploring off-label uses of 510(k) devices in children, developing pediatric tracking of procedures, improving pediatric postmarket surveillance, and conducting long term follow-up research studies on new technologies are all medically reasonable but also expensive tasks. At times of financial constraints in health care, it is still debatable who is to pay for such endeavors. The above mentioned challenges inherent to the pediatric congenital heart disease population continue to exist. When a stent implanted off-label is considered standard of care, supported by an AHA statement indication,[1] is reimbursed by insurance and perceived as a highly successful procedure, where is the incentive to comply with extensive registries, Institutional Review Board research regulations and study protocols?

Multicenter studies evaluating the outcomes and adverse events related to pediatric cardiac catheterization procedures were relatively uncommon in the past.[17] In more recent years, despite challenges mentioned above, multiple collaborative efforts have been successful in this regard, such as the MAGIC Catheterization Outcomes Project,[18] the Congenital Cardiac Catheterization Outcomes Project (C3PO),[19] as well as specific registries on certain interventions conducted by the Congenital Cardiovascular Interventional Study Consortium.[20] The IMPACT Registry™ currently launching in the United States[21] aims to enroll all children and adults with congenital heart disease undergoing diagnostic or interventional cardiac catheterizations. These registries have the potential to achieve successful participation of large numbers of centers and operators. They accumulate a significant volume of pediatric cardiac interventional procedural outcomes data. Maximum center participation can be incentivized by offering institutions the ability to collect and analyze data for performance measurement, include an internal periodic reporting tool on quality and outcomes, benchmarking, generation of quality improvement projects, eligibility for Maintenance of Certification recertification requirements for American Board of Pediatrics diplomats, and potential for incorporating features to facilitate claims reimbursements, as well as registry recognition by publically valued quality of care ranking tools. The success of these efforts will likely change the evidence on which future cardiac catheterization indications statements will be based 10 years from now.

As medicine evolves into an era focused on healthcare quality, improvement of clinical outcomes, and cost-effective delivery of care, pediatric interventional cardiology will increasingly be scrutinized. One hopes that in addition to implementing large national registries, research efforts will be solid and ongoing to provide the foundation for future developments as well as guidelines based on strong scientific evidence and supported by an increased percentage of evidence level A and B rather than C.

This new AHA scientific statement[1] helps define the standard of cardiovascular care in the United States in 2011 for the field of pediatric interventional cardiology. Although the evidence base supporting these recommendations is fragmented, the document[1] is the result of a rigorous and extensive review of the literature and underwent extensive peer review. The authors have performed a valuable task in collating and objectively assessing the current state of the art interventional therapies to result in a strong set of recommendations that should be rapidly and widely accepted by the providers and the payers of health care.