A Bayesian Re-analysis of the STRESS Trial

Abstract

Background: Prophylactic steroids are often used to reduce the systemic inflammatory response to cardiopulmonary bypass in infants undergoing heart surgery. The STRESS trial found that the odds of a worse outcome did not differ between infants randomized to methylprednisolone (n=599) versus placebo (n=601) (adjusted odds ratio [OR], 0.86; P=0.14). However, secondary analyses showed possible benefits with methylprednisolone. To investigate further using a different probabilistic approach, we re-analyzed the STRESS trial using Bayesian analytics.

Methods: We used a covariate-adjusted proportional odds model using the original STRESS trial primary endpoint, a ranked composite of death, transplant, major complication and post-op length of stay. We performed Markov Chain Monte Carlo simulations to assess the probability of benefit (OR <1) versus harm (OR >1). Primary analysis assumed a neutral probability of benefit versus harm with weak prior belief strength (nearly non-informative prior distribution). To illustrate magnitude of effect, we calculated predicted risk of death, transplant or major complications for methylprednisolone and placebo. Sensitivity analyses evaluated pessimistic (5%-30% prior likelihood of benefit), neutral and optimistic (70%-95%) prior beliefs, and controlled strength of prior belief as weak (30% variance), moderate (15%) and strong (5%). A secondary analysis derived empirical priors using data from four previous steroid trials.

Results: The posterior probability of any benefit from methylprednisolone was 92% and probability of harm was 8%. Composite death or major complication occurred in 18.8% of subjects with an absolute risk difference of -2% (95% CI -3%, +1%) for methylprednisolone. Each of 9 sensitivity analyses demonstrated greater probability of benefit than harm in the methylprednisolone group with 8 of 9 demonstrating >80% probability of benefit and ≥1% absolute difference in risk of death, transplant or major complications. In secondary analysis deriving priors from previous steroid trials, results were consistent with a 95% posterior probability of benefit.

Conclusion: Our Bayesian re-analysis of the STRESS trial, using a range of prior beliefs, demonstrated a high probability that perioperative methylprednisolone reduces the risk of death or major complications in infants undergoing cardiopulmonary bypass compared with placebo. This more in-depth analysis expands the initial clinical evaluation of methylprednisolone provided by the STRESS trial.

Trial registration: Clinicaltrials.gov: NCT03229538 (https://clinicaltrials.gov/study/NCT03229538).

Keywords: cardiopulmonary bypass; congenital heart disease; perioperative glucocorticoids; registry; trial.