The decades-old question of whether steroids should be used in infants undergoing heart surgery to reduce inflammation from cardiopulmonary bypass remains unanswered, despite the heft of the largest pediatric heart surgery trial to date.
Results from the STRESS trial, which included 1200 babies yet to reach their first birthday, show perioperative methylprednisolone did not reduce the likelihood of a ranked composite of outcomes including operative death, heart transplantation, and 13 other major complications compared with placebo after covariate adjustment (adjusted odds ratio [OR] 0.86; 95% CI, 0.71 - 1.05).
There was no difference in the primary endpoint components of operative mortality (2% methylprednisolone group vs 2.8% placebo), a composite of mortality and major complications (17.2% vs 20.3%), and prolonged mechanical ventilation (6.8% vs 8.5%).
Babies who received methylprednisolone were also more likely to have high blood glucose levels, a known stress response to surgery, with 19% requiring postoperative insulin vs 6.7% with placebo (P < .001), according to results published November 6 in the New England Journal of Medicine.
In a secondary analysis, however, methylprednisolone reduced the likelihood of the primary endpoint when analyzed without covariate adjustment (OR, 0.82; 95% CI, 0.67 - 1.00) and was a "win" for babies in a win ratio analysis of matched pairs of patients (1.15; 95% CI, 1.00 - 1.32).
The odds of bleeding requiring reoperation were also significantly lower in the steroid group (7 vs 21 events; aOR, 0.34; P = .016).
"There's a lot of signal to suggest a small benefit from steroids, so in talking with our surgeons, I suggested that we continue to use them," principal investigator Kevin D. Hill, MD, Duke Pediatric and Congenital Heart Center in Durham, North Carolina, told theheart.org | Medscape Cardiology.
"But I do think that there's potential to use them in a more targeted fashion for patients who have more potential for benefit and less potential for side effects," he added.
Subgroup analyses suggested relatively greater benefit for infants undergoing less complex operations (STAT 1-3 on a 5-point scale), those with longer cardiopulmonary bypass times, and those who were born premature.
Dearth of Evidence
"We love to see a trial where treatments just hit a home run and are something we can do for our patients that makes a really big difference. Unfortunately, this isn't the case here," Larry A. Allen, MD, University of Colorado, Aurora, told theheart.org | Medscape Cardiology.
"This is one of these trials where it trends in the right direction but isn't statistically significant, so the result is there may be a small benefit, it's not big, and it probably doesn't cause much harm," he said. "So we're left with saying current practice is probably reasonable."
In presenting the findings at the American Heart Association Scientific Sessions 2022, Hill pointed out that earlier studies of perioperative corticosteroids in children suggested a mortality benefit, whereas a recent meta-analysis reported no difference in outcomes other than improved fluid balance at 24 and 36 hours, but was underpowered with just 768 children enrolled over four decades.
Not surprising, 52% of neonates undergoing cardiac surgery receive steroids and 48% do not, he said.
STRESS was a pragmatic trial recruiting children younger than 1 year of age undergoing elective cardiac surgery with cardiopulmonary bypass at 24 sites in the Society of Thoracic Surgeons Congenital Surgery database. An ancillary database was also created to track results.
A total of 1263 patients were randomly assigned to methylprednisolone 30 mg/kg or placebo, of which 1200 received study treatment. The median age was 126 days and three quarters were White.
"Our pragmatic 'trial within a registry' design was a success with a total cost of approximately $3 million or per patient of $2400, which is substantially lower than any traditional trial," Hill said.
The Future of Pediatric Trials
Invited discussant Stephanie Fuller, MD, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, noted that the trial took place over 6 years at 24 centers and the "estimated costs were under $3 million and you estimate the cost of a conventional trial similar to this would be approximately $13 million. This is truly the future of cardiovascular pediatric trials."
Patrick O'Gara, MD, from Brigham and Women's Hospital, Boston, Massachusetts, and co-moderator of the late-breaking session, said in an interview that "one of the most important things about that trial was the demonstration that we can actually do a randomized trial on a registry-based format and to move forward in the field of pragmatic trials that answer these major clinical questions."
As to how the results will be interpreted, "I think it will boil down to parochial preferences, as many of these things do."
Alistair Phillips, MD, Cleveland Clinic Miller Family Heart and Vascular Institute, Ohio, told theheart.org | Medscape Cardiology that STRESS is an "important and very well done study with the major issue being the heterogeneity of the population and the variability of care from institution to institution, from anesthesia techniques to perfusion techniques, and from blood management techniques to medical management postoperatively. Further studies to look at specific populations are warranted."
The study was funded by the Centers for Advancing Translational Sciences and from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Hill reports no relevant industry relationships.
N Engl J Med. Published November 6, 2022. Full text
American Heart Association (AHA) Scientific Sessions 2022. Presented November 6, 2022.
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Cite this: Steroids Fail to Deliver Clear Benefits in Infant Heart Surgery - Medscape - Nov 07, 2022.