International integrated database for the evaluation of severe sepsis (INDEPTH): Clinical evaluation committee report on the safety of drotrecogin alfa (activated) therapy

Objective: INDEPTH is an integrated database of five trials enrolling patients with severe sepsis. It was created to better understand safety of drotrecogin alfa (activated) (DrotAA) in severe sepsis, examine factors impacting management of sepsis patients, and improve design of future clinical trials. The results of safety analyses are reported. Research design and methods: INDEPTH patients received DrotAA (24 μg/kg/h, n = 3228) or placebo (n = 1231) for 96 h. Following predefined criteria for blinded review, a clinical evaluation committee reviewed all serious adverse events (SAEs) during the 28-day study periods. As this was a retrospective analysis of five different trials with slightly different inclusion criteria and SAE reporting, propensity scores were computed and included as covariates to adjust for potential baseline imbalances and permit integration of patient data. Results: During the 28-day study period, 13.2% of DrotAA-treated patients experienced at least one SAE versus 13.8% of placebo patients. Serious bleeding events (SBEs) occurred in 5.6% of DrotAA-treated versus 2.0% of placebo patients (p < 0.001) and non-bleeding-related SAEs in 8.6% and 12.5%, respectively (p < 0.001). Fewer thrombotic events (p = 0.006; primarily myocardial infarction (MI), p = 0.014, stroke, p = 0.099; and arrhythmias, p < 0.001) were observed in DrotAA-treated patients versus placebo, although reduction in MI was no longer significant with propensity adjustment. Mortality remained numerically lower in DrotAA-treated patients versus placebo, regardless of whether the SAE was bleeding (70/182, 38.5% vs. 13/25, 52.0%) or non-bleeding-related (82/279, 29.4% vs. 64/154, 41.6%). Conclusions: Although SBEs occurred more often, non-bleeding SAEs (e.g., arterial thrombotic events, arrhythmias) occurred less frequently with DrotAA. Overall, incidence of SAEs was not increased with DrotAA.