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The protein C pathway: implications for the design of the RESPOND study.

Vangerow B, Shorr AF, Wyncoll D, Janes J, Nelson DR, Reinhart K - Crit Care (2007)

Bottom Line: The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome.The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C.The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Eli Lilly Critical Care Europe, Air Center, 1214 Vernier/Geneva, Switzerland. vangerow_burkhard@lilly.com

ABSTRACT
The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome. Data from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial indicate that administration of drotrecogin alfa (activated; DrotAA) leads to an increase in endogenous protein C levels in severe sepsis patients. In a group as heterogeneous as sepsis patients, the currently approved dose and duration of administration (24 mug/kg per hour for 96 hours) might not be optimal in some individuals. The RESPOND (Research Evaluating Serial Protein C levels in severe sepsis patients ON Drotrecogin alfa [activated]) trial is a phase II study being conducted to explore the use of endogenous protein C level as both a biomarker and a steering parameter for administration of DrotAA. Eligible patients will receive DrotAA either at the normal, currently approved dose and duration of administration ('standard therapy') or at a higher dose with variable infusion duration or variable infusion duration only ('alternative therapy'). The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C. The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.

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Mortality by end of infusion protein C level in PROWESS [9] and ENHANCE [10]. Patients were included if they had a baseline protein C measure. Day 4 protein C was classified as end of infusion. If the protein C level on day 4 was not available, then last observation carried forward values were used for classification. In this scale, >80% is a normal protein C level and ≤40% is half or less of the lower limit of normal. DrotAA, drotrecogin alfa (activated); ENHANCE, Extended Evaluation of Recombinant Human Activated Protein C, drotrecogin alfa (activated); N, total number of patients in each group; PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.
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Figure 3: Mortality by end of infusion protein C level in PROWESS [9] and ENHANCE [10]. Patients were included if they had a baseline protein C measure. Day 4 protein C was classified as end of infusion. If the protein C level on day 4 was not available, then last observation carried forward values were used for classification. In this scale, >80% is a normal protein C level and ≤40% is half or less of the lower limit of normal. DrotAA, drotrecogin alfa (activated); ENHANCE, Extended Evaluation of Recombinant Human Activated Protein C, drotrecogin alfa (activated); N, total number of patients in each group; PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.

Mentions: Data from PROWESS and ENHANCE demonstrated that higher end-of-infusion protein C levels are associated with lower mortality (Figure 3). PROWESS also demonstrated that, compared with placebo patients, fewer DrotAA patients had severe protein C deficiency at the end of the infusion (166 patients [19.5%] versus 217 patients [25.8%]), and a greater number of DrotAA patients had normal protein C levels at the end of the infusion (290 patients [34.1%] versus 211 patients [25.1%], P < 0.001). These findings were observed even though the DrotAA group had a greater number of patients with severe protein C deficiency at baseline than did the placebo group (330 patients [38.8%] versus 285 patients [33.9%]). The protein C levels in DrotAA patients also rose more rapidly than did those in placebo patients (Figure 4) and were significantly higher on each day of the infusion period. There are a number of potential explanations for the observed effect of DrotAA administration on endogenous protein C levels. It could be due to decreased consumption or degradation of endogenous protein C as the consumptive coagulopathy is inhibited; however, this may not be very relevant because the levels of other coagulation factors such as antithrombin III or protein S are not specifically increased with DrotAA treatment. Alternatively, there might be a direct effect of protein C on hepatic synthesis.


The protein C pathway: implications for the design of the RESPOND study.

Vangerow B, Shorr AF, Wyncoll D, Janes J, Nelson DR, Reinhart K - Crit Care (2007)

Mortality by end of infusion protein C level in PROWESS [9] and ENHANCE [10]. Patients were included if they had a baseline protein C measure. Day 4 protein C was classified as end of infusion. If the protein C level on day 4 was not available, then last observation carried forward values were used for classification. In this scale, >80% is a normal protein C level and ≤40% is half or less of the lower limit of normal. DrotAA, drotrecogin alfa (activated); ENHANCE, Extended Evaluation of Recombinant Human Activated Protein C, drotrecogin alfa (activated); N, total number of patients in each group; PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.
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Related In: Results  -  Collection

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Figure 3: Mortality by end of infusion protein C level in PROWESS [9] and ENHANCE [10]. Patients were included if they had a baseline protein C measure. Day 4 protein C was classified as end of infusion. If the protein C level on day 4 was not available, then last observation carried forward values were used for classification. In this scale, >80% is a normal protein C level and ≤40% is half or less of the lower limit of normal. DrotAA, drotrecogin alfa (activated); ENHANCE, Extended Evaluation of Recombinant Human Activated Protein C, drotrecogin alfa (activated); N, total number of patients in each group; PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.
Mentions: Data from PROWESS and ENHANCE demonstrated that higher end-of-infusion protein C levels are associated with lower mortality (Figure 3). PROWESS also demonstrated that, compared with placebo patients, fewer DrotAA patients had severe protein C deficiency at the end of the infusion (166 patients [19.5%] versus 217 patients [25.8%]), and a greater number of DrotAA patients had normal protein C levels at the end of the infusion (290 patients [34.1%] versus 211 patients [25.1%], P < 0.001). These findings were observed even though the DrotAA group had a greater number of patients with severe protein C deficiency at baseline than did the placebo group (330 patients [38.8%] versus 285 patients [33.9%]). The protein C levels in DrotAA patients also rose more rapidly than did those in placebo patients (Figure 4) and were significantly higher on each day of the infusion period. There are a number of potential explanations for the observed effect of DrotAA administration on endogenous protein C levels. It could be due to decreased consumption or degradation of endogenous protein C as the consumptive coagulopathy is inhibited; however, this may not be very relevant because the levels of other coagulation factors such as antithrombin III or protein S are not specifically increased with DrotAA treatment. Alternatively, there might be a direct effect of protein C on hepatic synthesis.

Bottom Line: The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome.The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C.The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Eli Lilly Critical Care Europe, Air Center, 1214 Vernier/Geneva, Switzerland. vangerow_burkhard@lilly.com

ABSTRACT
The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome. Data from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial indicate that administration of drotrecogin alfa (activated; DrotAA) leads to an increase in endogenous protein C levels in severe sepsis patients. In a group as heterogeneous as sepsis patients, the currently approved dose and duration of administration (24 mug/kg per hour for 96 hours) might not be optimal in some individuals. The RESPOND (Research Evaluating Serial Protein C levels in severe sepsis patients ON Drotrecogin alfa [activated]) trial is a phase II study being conducted to explore the use of endogenous protein C level as both a biomarker and a steering parameter for administration of DrotAA. Eligible patients will receive DrotAA either at the normal, currently approved dose and duration of administration ('standard therapy') or at a higher dose with variable infusion duration or variable infusion duration only ('alternative therapy'). The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C. The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.

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Related in: MedlinePlus