Symptomatic Tetralogy of Fallot: New Multicenter Study Compares Outcomes from Primary and Staged Repair Management Strategies

April 6, 2021

Published in February in the Journal of the American College of Cardiology, a new multicenter study1 on the management of symptomatic tetralogy of Fallot (sTOF) in neonates brings to light fresh findings on outcomes of primary versus staged repair approaches. Bryan H. Goldstein, MD, Director of Cardiac Catheterization & Intervention at the Heart Institute at UPMC Children’s Hospital of Pittsburgh, was lead author of the study that examined data on outcomes from nine U.S. pediatric congenital heart programs that are members of the Congenital Cardiac Research Collaborative.*

Management strategies for sTOF in neonates fall into two categories – primary repair (PR), which definitively corrects the heart defect during a single operation – and staged repair (SR), consisting of early palliative intervention followed by subsequent definitive surgical correction. The approach taken by individual centers has typically been dictated by local expertise and capabilities as well as patient-specific characteristics and risk profile.

Past studies comparing outcomes of each approach have been limited by inadequate sample size, incomplete data availability, or insufficient follow-up. This study, the first of its kind from a multicenter collaborative, was able to leverage extensive data collection from large congenital heart programs to overcome these limitations. The CCRC study conducted by Dr. Goldstein and colleagues’ is a multicenter retrospective analysis of sTOF cases from CCRC centers from 2005 to November 2017. A total of 572 cases were examined, including 342 SR cases and 230 PR cases.

A number of important, new findings were ascertained from the study, in addition to the identification of additional questions, yet to be answered. Ongoing work with this CCRC dataset should help provide answers to some of these meaningful questions.

"An important takeaway from our study is that there are trade-offs relative to outcomes between the staged and primary repair approaches to management of symptomatic neonatal TOF. Furthermore, we do not yet know all of the implications of the discrepancies between the two groups or how they manifest later in life, particularly with regard to longer-term effects on patient health and development" says Dr. Goldstein. 

Summary of Key Findings

Mortality

Within the SR and PR cohorts, medium-term mortality rates were comparable and significant – 10.2% and 7.4% – at 4.3 years median follow-up. These rates were not significantly different between groups.

“This is not a trivial finding,” says Dr. Goldstein. “Unfortunately, despite substantial improvements in perioperative care, there is still a significant risk of death early after treatment of symptomatic neonatal tetralogy of Fallot, and parents and families should be counseled accordingly.” 

The study also looked at mortality in the early postoperative period, where there was a significant benefit found to the SR strategy, at each of the two component stages (palliation and definitive repair). This has important implications for congenital heart programs, which are judged in part by early postoperative survival (U.S. News and World Report survey metric).  

However, while in-hospital mortality and complications were lower in the SR group, when the entirety of the SR pathway was compared to PR, there was no survival advantage found.  

Cumulative Morbidity and Neonatal Morbidity

A crucial aspect of the study examined a range of procedural morbidities, as well as cumulative morbidity between the PR and SR cohorts.

“Our analysis found a clear benefit in terms of neonatal morbidities with the staged repair pathway. We found a reduced burden of exposure to potentially toxic exposures such as anesthesia, cardio-pulmonary bypass and cross-clamp times, ICU and hospital length of stay, duration of mechanical ventilatory support, and others,” says Dr. Goldstein.

However, the cumulative burden of exposure to these morbidities was generally lower for the primary repair group. Likewise, reinterventions were more common in the staged repair group, but this largely reflected reinterventions before definitive repair. Following definitive repair, there was no difference in the rate of reintervention.

"We know that the early neonatal period is crucial to later neurodevelopmental outcomes.  Less exposure to treatment toxicities in the neonatal time period should confer better outcomes in this respect. However, greater cumulative exposure to morbidity burden is also deleterious. At this point, we don’t know with certainty how the differential morbidity profiles of staged and primary repair will impact late neurodevelopmental outcomes,” says Dr. Goldstein.

Follow-Up Research: Answering Unanswered Questions

Dr. Goldstein and colleagues have several immediate follow-up studies either in early phase work or in planning. The first will track neurodevelopmental outcomes in both cohorts from the initial retrospective study. A second study, accepted for presentation at the upcoming American College of Cardiology Scientific Sessions, examined the cost of care of the two care pathways to understand the potentially disparate economic impact of these management strategies for neonatal symptomatic TOF. Multiple additional studies are in the works.

"Our study group also has a keen interest in longer-term outcomes related to growth of the pulmonary arteries and function of the right ventricle and pulmonary valve, to name a few consequential anatomic features. These are important late characteristics that undoubtedly have impact on functional outcomes following repair of sTOF, for which we have minimal data. Answering these questions is another of our research priorities," says Dr. Goldstein.

Related Trials and Longitudinal Studies

In related work, in part developed as a consequence of the sTOF study, Dr. Goldstein and colleagues have been making preparations for a prospective randomized clinical trial for patients with ductal-dependent pulmonary blood flow. Patients in this trial will be randomized to either receive a Blalock-Thomas-Taussig (BTT) shunt or patent ductus arteriosus (PDA) stent. Patients enrolled in the trial, along with patients eligible for the trial but whom do not enroll, will be monitored though the CCRC Registry, a new registry designed to track the short- and long-term outcomes of these patients. The CCRC Registry is a member of Cardiac Networks United, a network of congenital heart disease-focused registries that improves efficiency through data linkages. The COMPASS trial, and components of the CCRC Registry, are funded by the National Institutes of Health National Heart, Lung, and Blood Institute, run under the auspices of the Pediatric Heart Network, and led by members of the CCRC. The new trial and registry are slated to begin enrolling patients in Fall 2021.

Reference

The complete study and its findings may be found using the following reference.
1. Goldstein BH, Petit CJ, Qureshi AM, et al. Comparison of Management Strategies for Neonates With Symptomatic Tetralogy of Fallot. J Am Coll Cardiol. 2021; 77(8): 1093-1106.

About Dr. Goldstein

Bryan H. Goldstein, MD, is an Associate Professor of Pediatrics at the University of Pittsburgh School of Medicine, and Director of the Cardiac Catheterization Laboratory in the Heart Institute at UPMC Children’s Hospital of Pittsburgh. Dr. Goldstein also is co-founder and vice president of the Congenital Cardiac Research Collaborative (CCRC), a multicenter academic collaborative that fosters research and quality improvement efforts amongst a growing coalition of leading North American congenital heart centers. The CCRC focuses on conducting outcomes research following surgical and transcatheter interventions for congenital heart disease. In early 2020, UPMC Children’s became the 10th member of the CCRC. 

*Note: UPMC Children's became a member of the CCRC after this study was conducted. As such, data from its outcomes of sTOF patients are not included in this analysis.