1. Population Health Research Institute Hamilton Health Sciences/McMaster University Hamilton, Canada Steroids In caRdiac Surgery (SIRS) Trial SIRS was funded by grants from the Canadian Institutes of Health Research (CIHR) and the Canadian Network and Centre for Trials Internationally (CANNeCTIN)

2. Trial Flow Diagram Randomized (n = 7,507) Allocated to steroid* (n = 3,755) Allocated to Placebo (n = 3,752) Analyzed by intention-to-treat (n = 3,755) Complete follow-up data (n = 3,754) Analyzed by intention-to-treat (n = 3,755) Complete follow-up data (n = 3,754) Analyzed by intention-to-treat (n = 3,752) Complete follow-up data (n = 3,751) Analyzed by intention-to-treat (n = 3,752) Complete follow-up data (n = 3,751) Lost to follow-up (n = 1) Did not receive study drug (n = 105) Lost to follow-up (n = 1) Did not receive study drug (n = 105) Lost to follow-up (n = 0) Did not receive study drug (n = 106) Lost to follow-up (n = 0) Did not receive study drug (n = 106) *500 mg IV Methylprednisolone given intra-operatively

3. Co-Primary Outcomes (30 days) 30-Day OutcomeSteroidPlaceboRR (95% CI)p-value First Co-Primary - Death 155 (4.1)176 (4.7)0.88 (0.71-1.09)0.23 Second Co-Primary - Composite death, MI, stroke, new renal failure, respiratory failure 913 (24.3)875 (23.3)1.04 (0.96-1.13)0.31 Components of Composite MI 508 (13.5) 419 (11.2) 1.21 (1.07-1.37) 0.001 Stroke72 (1.9)80 (2.1)0.90 (0.66-1.23)0.51 New Renal Failure107 (2.8)114 (3.0)0.94 (0.72-1.22)0.62 Respiratory Failure343 (9.1)375 (10.0)0.91 (0.79-1.05)0.20

4. Conclusion Methylprednisolone does not reduce death or major morbidity at 30 days for high-risk patients undergoing cardiac surgery with the use of cardiopulmonary bypass. Methylprednisolone increases the risk of early post- operative myocardial infarction, defined by CK-MB biomarker release.

5. Implications Methylprednisolone should not be administered prophylactically to high-risk patients undergoing cardiac surgery with the use of cardiopulmonary bypass. Further work is necessary to understand the mechanism of steroid-driven myocardial infarction.