A Bayesian Re-analysis of the Steroids to Reduce Systemic Inflammation after Infant Heart Surgery (STRESS) Trial
Insights
Prophylactic methylprednisolone shows a high probability of benefit for infants undergoing heart surgery, with a low risk of harm. This Bayesian re-analysis of the STRESS trial provides deeper insights into its efficacy.
Area of Science:
- Pediatric Cardiac Surgery
- Pharmacology
- Biostatistics
Background:
- Prophylactic steroids, specifically methylprednisolone, are commonly administered to mitigate systemic inflammatory responses during cardiopulmonary bypass in pediatric heart surgery.
- The original STRESS trial indicated no significant difference in worse outcomes between methylprednisolone and placebo groups in primary analyses.
- However, secondary analyses suggested potential benefits, prompting further investigation into methylprednisolone's efficacy.
Purpose of the Study:
- To re-analyze the STRESS trial data using Bayesian analytics to precisely assess the probability of benefit from prophylactic methylprednisolone.
- To determine the likelihood of benefit versus harm, ensuring potentially effective therapies are not overlooked.
Main Methods:
- Bayesian analysis was applied to the STRESS trial's primary composite outcome (death, transplant, major complications, post-operative length of stay).
- Markov Chain Monte Carlo simulations (10 simulations, 2000 iterations, 1000 burn-in) were used to evaluate posterior distributions and probability of benefit (OR<1).
- Sensitivity analyses explored various prior beliefs (pessimistic, neutral, optimistic) and prior belief strengths (weak, moderate, strong).
Main Results:
- The primary Bayesian analysis yielded a 91% probability of benefit and a 9% probability of harm for methylprednisolone.
- The composite outcome of death or major complication occurred in 18.8% of subjects, with an absolute risk difference of -2% favoring methylprednisolone.
- Nine sensitivity analyses consistently showed a higher probability of benefit than harm, with 8 demonstrating >80% probability of benefit and ≥1% absolute risk reduction.
Conclusions:
- The re-analysis indicates a high probability of benefit and low likelihood of harm associated with prophylactic methylprednisolone in this patient population.
- These findings offer a more comprehensive understanding of methylprednisolone's role, expanding upon the initial STRESS trial evaluation.
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 likelihood of a worse outcome did not differ between infants randomized to methylprednisolone (n=599) versus placebo (n=601) in a risk-adjusted primary analysis (adjusted odds ratio [OR], 0.86; 95% CI, 0.71 to 1.05; P=0.14). However, secondary analyses showed possible benefits with methylprednisolone. To ensure that a potentially efficacious therapy is not unnecessarily avoided, we re-analyzed the STRESS trial using Bayesian analytics to assess the probability of benefit.
Methods:
Our Bayesian analysis used the original STRESS trial primary outcome measure, a hierarchically ranked composite of death, transplant, major complications and post-operative length of stay. We evaluated probability of benefit (OR<1) versus harm (OR>1) by comparing the posterior distribution of the OR assuming a neutral probability of benefit versus harm with weak prior belief strength (nearly non-informative prior distribution). Reference results were calculated under the vague prior distribution. To convey magnitude of effect we used model parameters to calculate a predicted risk of death, transplant or major complications for methylprednisolone and placebo. Analyses consisted of 10 Markov Chain Monte Carlo simulations, each consisting of 2000 iterations with a 1000 iteration burn-in to ensure proper posterior convergence. 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%).
Results:
In primary analysis, the posterior probability of benefit from methylprednisolone was 91% and probability of harm was 9%. Composite death or major complication occurred in 18.8% of trial subjects with an absolute risk difference of -2% (95% CI -3%, +1%) associated with 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.
Conclusion:
Probability of benefit with prophylactic methylprednisolone is high and harm is unlikely. This more in-depth analysis of the data expands the initial clinical evaluation of methylprednisolone provided by the STRESS trial.
