To better understand treatment risks and benefits of drotrecogin alfa (activated) (DrotAA), a clinical evaluation committee evaluated all serious adverse events (SAEs), occurring across five clinical trials [conducted by a single sponsor (Eli Lilly and Company) and integrated into single database, INDEPTH (4459 patients)] in patients with severe sepsis.
We examined all SAEs which occurred during infusion (n=277) from 1231 placebo and 3228 DrotAA patients. Investigators were blinded to treatment assignment.
Total SAE rates were similar. More bleeding but fewer non-bleeding SAEs occurred in patients receiving DrotAA. Approximately half of the SAEs during the 28-day study period were reported at a time when DrotAA (and also placebo) was not being infused and are considered likely unrelated, given the known short half-life of the drug. (See Table 1) SAEs occurred with similar frequency in both treatment arms and notably 93.8% of the DrotAA and 93.7% of the placebo treated patients did not experience an SAE during the infusion. Mortality was still lower in DrotAA treated patients compared to placebo in patients experiencing a bleeding or non-bleeding SAE. (See Table 1).
Although DrotAA is associated with an increased bleeding risk, it was also associated with fewer thrombotic events and the overall rate of SAEs was similar. Mortality was lower in DrotAA treated patients even in the presence of a bleeding or a non-bleeding event. Adjustment for the use of multiple studies with propensity scores did not affect these conclusions.
Benefit of treatment with DrotAA outweights the risks associated with adverse events and improves survival.
Table 1SAEs During Infusion PeriodDrotAAPlacebop Value**All SAEs199 (6.16%)78 (6.34%)0.832Non Bleeding Events113 (3.50%)72 (5.85%)<0.001Arterial Thrombotic Events*26 (0.81%)22 (1.79%).0045Bleeding Events101 (3.13%)9 (0.73%)<0.001CNS Bleeding15 (0.46)1(0.08)0.087****
MI, stroke without hemorrhage, other arterial thrombotic events
Robert Levine, Consultant fee, speaker bureau, advisory committee, etc. Advisory panel fee.