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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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Change in protein C levels and 28-day mortality in PROWESS patients [9]. DrotAA, 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 2: Change in protein C levels and 28-day mortality in PROWESS patients [9]. DrotAA, drotrecogin alfa (activated); N, total number of patients in each group; PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.

Mentions: Patients were classified as to whether they had normal protein C levels at baseline or had a deficiency in protein C, and whether they achieved normal protein C any time during infusion or had below normal levels at any time during infusion (Figure 2). In the group that was deficient in protein C at baseline, DrotAA patients were significantly more likely to improve to normal levels during infusion (P = 0.0001, by χ2 test); also, there was a trend (P = 0.14, by χ2 test) for more placebo patients with normal protein C levels at baseline than DrotAA patients to exhibit below normal levels. For patients with below normal baseline protein C that remained below normal during infusion, there was no significant difference in 28-day mortality rates (P = 0.24, by χ2 test) between treatment groups. Similarly, for patients with normal baseline protein C that remained normal during infusion, there was no significant difference in 28-day mortality rates (P = 0.59, by χ2 test) between treatment groups. Among those who improved from below normal protein C levels to above normal protein C levels, DrotAA patients tended to have a lower mortality (P = 0.07, by χ2 test). DrotAA patients also had lower mortality among those who had above normal levels that fell below normal during infusion (P = 0.054). These findings have the following implications. First, the DrotAA treatment effect may be reflected, at least in part, by the increase in numbers of patients presenting with normal protein C levels at the end of infusion, who have generally low mortality. Second, DrotAA benefits patients with normal protein C levels at baseline because it reduces their likelihood of becoming deficient or may help to restore levels to normal by the end of infusion. Third, the benefit of DrotAA treatment is largely confined to patients who are, or who will become, protein C deficient.


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)

Change in protein C levels and 28-day mortality in PROWESS patients [9]. DrotAA, drotrecogin alfa (activated); N, total number of patients in each group; PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2230608&req=5

Figure 2: Change in protein C levels and 28-day mortality in PROWESS patients [9]. DrotAA, drotrecogin alfa (activated); N, total number of patients in each group; PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.
Mentions: Patients were classified as to whether they had normal protein C levels at baseline or had a deficiency in protein C, and whether they achieved normal protein C any time during infusion or had below normal levels at any time during infusion (Figure 2). In the group that was deficient in protein C at baseline, DrotAA patients were significantly more likely to improve to normal levels during infusion (P = 0.0001, by χ2 test); also, there was a trend (P = 0.14, by χ2 test) for more placebo patients with normal protein C levels at baseline than DrotAA patients to exhibit below normal levels. For patients with below normal baseline protein C that remained below normal during infusion, there was no significant difference in 28-day mortality rates (P = 0.24, by χ2 test) between treatment groups. Similarly, for patients with normal baseline protein C that remained normal during infusion, there was no significant difference in 28-day mortality rates (P = 0.59, by χ2 test) between treatment groups. Among those who improved from below normal protein C levels to above normal protein C levels, DrotAA patients tended to have a lower mortality (P = 0.07, by χ2 test). DrotAA patients also had lower mortality among those who had above normal levels that fell below normal during infusion (P = 0.054). These findings have the following implications. First, the DrotAA treatment effect may be reflected, at least in part, by the increase in numbers of patients presenting with normal protein C levels at the end of infusion, who have generally low mortality. Second, DrotAA benefits patients with normal protein C levels at baseline because it reduces their likelihood of becoming deficient or may help to restore levels to normal by the end of infusion. Third, the benefit of DrotAA treatment is largely confined to patients who are, or who will become, protein C deficient.

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.

Show MeSH
Related in: MedlinePlus