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

Jean François Dhainaut, P. F. Laterre, J. M. Janes, A. Artigas, G. J. Beilman, I. A. Fein, L. F. Poli-de-Figueiredo, D. Heiselman, R. L. Levine, Roland Schein, M. Seneff, J. P. Sollet, J. Bailey, F. Booth, M. Cobas Meyer, D. R. Nelson, A. Sashegyi, S. Lowry

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)1187-1197
Number of pages11
JournalCurrent Medical Research and Opinion
Volume24
Issue number4
DOIs
StatePublished - Apr 1 2008

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Sepsis
Databases
Safety
Placebos
Therapeutics
Hemorrhage
Cardiac Arrhythmias
Myocardial Infarction
drotrecogin alfa activated
Propensity Score
Research Design
Stroke
Clinical Trials
Mortality
Incidence

Keywords

  • Clinical evaluation committee
  • Drotrecogin alfa (activated)
  • INDEPTH
  • Safety
  • Severe sepsis database

ASJC Scopus subject areas

  • Medicine(all)

Cite this

International integrated database for the evaluation of severe sepsis (INDEPTH) : Clinical evaluation committee report on the safety of drotrecogin alfa (activated) therapy. / Dhainaut, Jean François; Laterre, P. F.; Janes, J. M.; Artigas, A.; Beilman, G. J.; Fein, I. A.; Poli-de-Figueiredo, L. F.; Heiselman, D.; Levine, R. L.; Schein, Roland; Seneff, M.; Sollet, J. P.; Bailey, J.; Booth, F.; Cobas Meyer, M.; Nelson, D. R.; Sashegyi, A.; Lowry, S.

In: Current Medical Research and Opinion, Vol. 24, No. 4, 01.04.2008, p. 1187-1197.

Research output: Contribution to journalArticle

Dhainaut, JF, Laterre, PF, Janes, JM, Artigas, A, Beilman, GJ, Fein, IA, Poli-de-Figueiredo, LF, Heiselman, D, Levine, RL, Schein, R, Seneff, M, Sollet, JP, Bailey, J, Booth, F, Cobas Meyer, M, Nelson, DR, Sashegyi, A & Lowry, S 2008, 'International integrated database for the evaluation of severe sepsis (INDEPTH): Clinical evaluation committee report on the safety of drotrecogin alfa (activated) therapy', Current Medical Research and Opinion, vol. 24, no. 4, pp. 1187-1197. https://doi.org/10.1185/030079908X280563
Dhainaut, Jean François ; Laterre, P. F. ; Janes, J. M. ; Artigas, A. ; Beilman, G. J. ; Fein, I. A. ; Poli-de-Figueiredo, L. F. ; Heiselman, D. ; Levine, R. L. ; Schein, Roland ; Seneff, M. ; Sollet, J. P. ; Bailey, J. ; Booth, F. ; Cobas Meyer, M. ; Nelson, D. R. ; Sashegyi, A. ; Lowry, S. / International integrated database for the evaluation of severe sepsis (INDEPTH) : Clinical evaluation committee report on the safety of drotrecogin alfa (activated) therapy. In: Current Medical Research and Opinion. 2008 ; Vol. 24, No. 4. pp. 1187-1197.
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abstract = "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.",
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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, Roland

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 - 2008/4/1

Y1 - 2008/4/1

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.

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KW - Drotrecogin alfa (activated)

KW - INDEPTH

KW - Safety

KW - Severe sepsis database

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