TY - JOUR
T1 - International integrated database for the evaluation of severe sepsis (INDEPTH)
T2 - Clinical evaluation committee report on the safety of drotrecogin alfa (activated) therapy
AU - Dhainaut, Jean François
AU - Laterre, P. F.
AU - Janes, J. M.
AU - Artigas, A.
AU - Beilman, G. J.
AU - Fein, I. A.
AU - Poli-de-Figueiredo, L. F.
AU - Heiselman, D.
AU - Levine, R. L.
AU - Schein, R.
AU - Seneff, M.
AU - Sollet, J. P.
AU - Bailey, J.
AU - Booth, F.
AU - Cobas Meyer, M.
AU - Nelson, D. R.
AU - Sashegyi, A.
AU - Lowry, S.
PY - 2008/4
Y1 - 2008/4
N2 - 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.
AB - 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.
KW - Clinical evaluation committee
KW - Drotrecogin alfa (activated)
KW - INDEPTH
KW - Safety
KW - Severe sepsis database
UR - http://www.scopus.com/inward/record.url?scp=42549122251&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=42549122251&partnerID=8YFLogxK
U2 - 10.1185/030079908X280563
DO - 10.1185/030079908X280563
M3 - Article
C2 - 18348744
AN - SCOPUS:42549122251
SN - 0300-7995
VL - 24
SP - 1187
EP - 1197
JO - Current Medical Research and Opinion
JF - Current Medical Research and Opinion
IS - 4
ER -