Efficient Registry Approach Powers Practice-Shaping Infant Heart Surgery Trial

(Ground Picture/Shutterstock)

December 2, 2022

A randomized clinical trial of 1,200 infants undergoing surgery for congenital heart disease recently found that the anti-inflammatory steroid methylprednisolone, often given during these surgeries, did not reduce the risk of death or other severe outcomes any more than a placebo. The trial outcomes also suggested that infants in the steroid-treated group were more likely to need insulin to treat high blood sugar after surgery. These findings were published in the New England Journal of Medicine.

Funded by NIH, the researchers used an existing surgical data registry to conduct a large, statistically powerful trial in a relatively small, complex pediatric population more easily.

The multicenter Steroids to Reduce Systemic Inflammation after Infant Heart Surgery (STRESS) trial included infants younger than 1 year who received congenital heart disease surgery with cardiopulmonary bypass. At the time of surgery, researchers randomly assigned infants to receive either 30 mg/kg of methylprednisolone intended to reduce inflammation, or a placebo. The study was designed to test the effect of the steroid on a group of major complications, including death during initial hospitalization and heart transplantation during hospitalization.

After accounting for such factors as age, sex, or premature birth, infants given methylprednisolone did not have better surgical outcomes than those given a placebo and were much more likely to need insulin to treat high blood sugar after surgery.

“Whether or not to use steroids preventively in these babies is an important clinical question,” said NCATS Senior Clinical Advisor Josh Fessel, M.D., Ph.D. “The finding that prophylactic methylprednisolone does not improve postoperative outcomes in infants undergoing heart surgery could rapidly change care for these patients, given that use of steroids perioperatively has been common practice in pediatric care for these kinds of patients.”

Improving Heart Surgery Outcomes

About 30,000 operations for congenital heart disease are performed in the United States every year. Most are on infants younger than 1 year. Those heart surgeries require cardiopulmonary bypass that can cause severe systemic inflammation. Anti-inflammatory glucocorticoids, such as methylprednisolone, are often given as a precaution to reduce the risk of dangerous inflammatory responses during surgery.

Despite use based on their potential value, preventive glucocorticoids have shown no decrease in death in some large, randomized, controlled trials in adults undergoing cardiopulmonary bypass during cardiac surgery. Those trials also showed that the anti-inflammatory drugs’ use was linked to greater risks of heart tissue damage and increased blood sugar levels.

Testing preventive glucocorticoids’ value in children undergoing congenital heart disease surgery is particularly challenging, the study’s authors noted. The number of pediatric patients who receive such complex procedures is relatively small, as is the number of medical centers that perform such procedures. Conducting a large, randomized, placebo-controlled trial with the statistical power needed to determine the true value of preventive steroids in children is difficult.

Creative Solutions Shape Trial Design

Leveraging a congenital heart data registry and streamlining study operations contributed to more efficient enrollment and faster trial activation, long-standing issues that can drive up trial costs and even contribute to trial failure.

“Our trial was designed to minimize costs and establish a mechanism for more efficient trials in children with heart disease,” explained the study’s lead author, Kevin D. Hill, M.D., of the Duke Clinical Research Institute.

To boost trial enrollment and deliver statistically robust results, the investigators collected the STRESS trial’s data through an extensive established registry, rather than collecting data only for this trial. The registry they chose — the Society of Thoracic Surgeons’ Congenital Heart Surgery Database — contains more than 600,000 congenital heart surgery procedure records, with more than 1,000 contributing doctors.

STRESS also used the clinical trial resources of the NCATS’ Clinical and Translational Science Awards (CTSA) Program to streamline study operations. For example, working with the CTSA Program’s Trial Innovation Network, the trial’s 24 U.S. congenital heart disease centers used the Streamlined, Multisite, Accelerated Resources for Trials (SMART IRB) Platform and IRB Exchange to reduce the time to reach enrollment targets and the time to prepare all 24 sites for the trial.

The costs for a registry-based approach were about a third of the costs of a traditionally designed trial, and this approach helped researchers meet their large enrollment target. They estimated that at least 1,200 participants were needed to determine whether the steroid improved outcomes, compared with a placebo. The trial’s final analysis included exactly 1,200 infants: 599 who received methylprednisolone, and 601 who received the placebo.

Results May Point to Promise in Subgroups

Despite the top-level findings, subanalyses did show evidence of a possible benefit for some infants, including those whose operations were less complex and those who were on cardiopulmonary bypass longer or born prematurely.

“Based on the results of our subgroup analyses, we need to hone in on patients who may actually benefit most from steroid use,” said the study’s senior author, Jennifer Li, M.D., of the Duke Clinical Research Institute. “Developing a targeted approach could maximize its benefit and minimize adverse effects.”

The STRESS trial was funded through NCATS and its CTSA Program, as well as the Eunice Kennedy Shriver National Institute of Child Health and Human Development.