Protein C zymogen in severe sepsis: a double-blinded, placebo-controlled, randomized study

Federico Pappalardo, Martina Crivellari, Ambra L. Di Prima, Nataliya Agracheva, Malgorzata Celinska-Spodar, Rosalba Lembo, Daiana Taddeo, Giovanni Landoni, Alberto Zangrillo

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Purpose: To determine whether protein C zymogen (protein C concentrates or human protein C) improves clinically relevant outcomes in adult patients with severe sepsis and septic shock. Methods: This is a randomized, double-blind, placebo-controlled, parallel-group trial that from September 2012 to June 2014 enrolled adult patients with severe sepsis or septic shock and high risk of death and of bleeding (e.g., APACHE II greater than 25, extracorporeal membrane oxygenation or disseminated intravascular coagulopathy). All patients completed their follow-up 90 days after randomization and data were analyzed according to the intention-to-treat principle. Follow-up was performed at 30 and 90 days after randomization. The primary endpoint was a composite outcome of prolonged intensive care unit (ICU) stay and/or 30-day mortality. Secondary endpoints included mortality. Results: The study was stopped early in a situation of futility for the composite outcome of prolonged ICU stay and/or 30-day mortality that was 79 % (15 patients) in the protein C zymogen group and 67 % (12 patients) in the placebo group (p = 0.40) and for a concomitant safety issue: ICU mortality was 79 % (15 patients) in the protein C zymogen group vs 39 % (7 patients) in the placebo group (p = 0.020), and 30-day mortality was 68 vs 39 % (p = 0.072). Conclusion: Protein C zymogen did not improve clinically relevant outcomes in severe sepsis and septic shock adult patients. Given its high cost and the potential increase in mortality, the use of this drug in adult patients should be discouraged.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalIntensive Care Medicine
DOIs
Publication statusAccepted/In press - Jun 25 2016

Fingerprint

Enzyme Precursors
Protein C
Sepsis
Placebos
Mortality
Septic Shock
Intensive Care Units
Random Allocation
Medical Futility
Extracorporeal Membrane Oxygenation
APACHE
Hemorrhage
Safety
Costs and Cost Analysis

Keywords

  • Critical care
  • Intensive care
  • Mortality
  • Protein C
  • Sepsis
  • Septic shock

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Protein C zymogen in severe sepsis : a double-blinded, placebo-controlled, randomized study. / Pappalardo, Federico; Crivellari, Martina; Di Prima, Ambra L.; Agracheva, Nataliya; Celinska-Spodar, Malgorzata; Lembo, Rosalba; Taddeo, Daiana; Landoni, Giovanni; Zangrillo, Alberto.

In: Intensive Care Medicine, 25.06.2016, p. 1-9.

Research output: Contribution to journalArticle

Pappalardo, Federico ; Crivellari, Martina ; Di Prima, Ambra L. ; Agracheva, Nataliya ; Celinska-Spodar, Malgorzata ; Lembo, Rosalba ; Taddeo, Daiana ; Landoni, Giovanni ; Zangrillo, Alberto. / Protein C zymogen in severe sepsis : a double-blinded, placebo-controlled, randomized study. In: Intensive Care Medicine. 2016 ; pp. 1-9.
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AU - Agracheva, Nataliya

AU - Celinska-Spodar, Malgorzata

AU - Lembo, Rosalba

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AU - Landoni, Giovanni

AU - Zangrillo, Alberto

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N2 - Purpose: To determine whether protein C zymogen (protein C concentrates or human protein C) improves clinically relevant outcomes in adult patients with severe sepsis and septic shock. Methods: This is a randomized, double-blind, placebo-controlled, parallel-group trial that from September 2012 to June 2014 enrolled adult patients with severe sepsis or septic shock and high risk of death and of bleeding (e.g., APACHE II greater than 25, extracorporeal membrane oxygenation or disseminated intravascular coagulopathy). All patients completed their follow-up 90 days after randomization and data were analyzed according to the intention-to-treat principle. Follow-up was performed at 30 and 90 days after randomization. The primary endpoint was a composite outcome of prolonged intensive care unit (ICU) stay and/or 30-day mortality. Secondary endpoints included mortality. Results: The study was stopped early in a situation of futility for the composite outcome of prolonged ICU stay and/or 30-day mortality that was 79 % (15 patients) in the protein C zymogen group and 67 % (12 patients) in the placebo group (p = 0.40) and for a concomitant safety issue: ICU mortality was 79 % (15 patients) in the protein C zymogen group vs 39 % (7 patients) in the placebo group (p = 0.020), and 30-day mortality was 68 vs 39 % (p = 0.072). Conclusion: Protein C zymogen did not improve clinically relevant outcomes in severe sepsis and septic shock adult patients. Given its high cost and the potential increase in mortality, the use of this drug in adult patients should be discouraged.

AB - Purpose: To determine whether protein C zymogen (protein C concentrates or human protein C) improves clinically relevant outcomes in adult patients with severe sepsis and septic shock. Methods: This is a randomized, double-blind, placebo-controlled, parallel-group trial that from September 2012 to June 2014 enrolled adult patients with severe sepsis or septic shock and high risk of death and of bleeding (e.g., APACHE II greater than 25, extracorporeal membrane oxygenation or disseminated intravascular coagulopathy). All patients completed their follow-up 90 days after randomization and data were analyzed according to the intention-to-treat principle. Follow-up was performed at 30 and 90 days after randomization. The primary endpoint was a composite outcome of prolonged intensive care unit (ICU) stay and/or 30-day mortality. Secondary endpoints included mortality. Results: The study was stopped early in a situation of futility for the composite outcome of prolonged ICU stay and/or 30-day mortality that was 79 % (15 patients) in the protein C zymogen group and 67 % (12 patients) in the placebo group (p = 0.40) and for a concomitant safety issue: ICU mortality was 79 % (15 patients) in the protein C zymogen group vs 39 % (7 patients) in the placebo group (p = 0.020), and 30-day mortality was 68 vs 39 % (p = 0.072). Conclusion: Protein C zymogen did not improve clinically relevant outcomes in severe sepsis and septic shock adult patients. Given its high cost and the potential increase in mortality, the use of this drug in adult patients should be discouraged.

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