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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.

Objective: To determine the efficacy and safety of extended drotrecogin alfa (activated) (DAA) therapy., Design: Multicentre, randomised, double-blind, placebo-controlled study., Setting: Sixty-four intensive care units in nine countries., Patients: Adults with severe sepsis and vasopressor-dependent hypotension after a 96-h infusion of standard DAA., Interventions: A total of 193 patients received an intravenous infusion of extended DAA 24 microg/kg/h or sodium chloride placebo for a maximum of 72 h., Measurements and Results: At extended therapy initiation (baseline), DAA-group patients had lower protein C levels (P = 0.23) and higher vasopressor requirements, particularly for the primary vasopressor used, norepinephrine (P = 0.03), compared with placebo-group patients. DAA treatment did not result in a difference in the primary outcome of time to resolution of vasopressor-dependent hypotension versus placebo (P = 0.419). However, few patients reached resolution (DAA 34%, placebo 40%) as most continued to require vasopressor support after 72 additional hours of treatment. Treatment did not reduce 28-day all-cause mortality and in-hospital mortality or improve organ function compared with placebo, although there was a lower percentage change in D-dimers (P < 0.001) and increases in protein C levels were numerically greater on extended infusion. There was no difference in serious adverse events including bleeding events., Conclusions: Extended DAA treatment did not result in more rapid resolution of vasopressor-dependent hypotension, despite demonstrating anticipated biological effects on D-dimer and protein C levels. A reduced planned sample size combined with baseline imbalances in protein C levels and vasopressor requirements may have limited the ability to demonstrate a clinical benefit.

Background: The purpose of this study was to characterize the usage patterns and clinical outcomes of DAA in Ontario and Quebec over a 1-year period., Methods: All hospitals with DAA on formulary in Ontario and Quebec were invited to participate. Consecutive patients who received DAA from 1 March 2003 to 29 February 2004 were identified retrospectively. Demographic, treatment, and outcome variables were collected via chart review. Descriptive statistics on relevant variables were performed, along with logistic regression to determine relevant risk factors for survival and bleeding., Results: Thirty-seven sites participated with a total of 261 courses of DAA administered. The overall mortality rate was 45%; age (> 65 years), multiple organ system failure (> 3), and nosocomial source of sepsis were predictors of mortality, whereas early DAA administration (< 12 h) was associated with lower mortality. Serious bleeding events occurred in 10% of the patients. Only 1 case (0.4%) of fatal intracranial bleed was observed. Multiple organ system failure (>/= 4)and relative contraindications to DAA were predictors of bleeding events., Interpretation: Mortality and bleeding complications associated with the use of DAA were higher than that reported in randomized trials but similar to other usage database. This may be due to the higher severity of illness seen in this cohort of patients. Modifiable risks associated with mortality and bleeding, such as time to treatment, and knowledge of relative contraindications should be targets of further research and future educational efforts in order to optimize the risk-to-benefit ratio of DAA.

Objective: To monitor the use of drotrecogin alfa activated (DrotAA) in Italy and its effects on patients' health., Design: Prospective pharmaco-surveillance program with a parallel non-randomized control group., Setting: The Ministry of Health required all intensive care units (ICUs) using DrotAA to participate in the pharmaco-surveillance program. Our control group was formed of patients eligible for treatment with DrotAA but who had not received it., Patients and Participants: The data we collected included basic demographic characteristics, indications, modalities of use, adverse events, and ICU mortality. We identified potentially non-collaborating centres on the basis of data on DrotAA purchasing by hospitals., Measurements and Results: From 2003 to 2006, 668 cases of treatment with DrotAA were reported. We estimate that 79.3% of all patients treated in Italy in this period were recruited. Off-label use was common. Delayed start was the main reason for off-label prescription. Bleeding during infusion occurred in 73 patients (10.9%). The ICU mortality was higher in patients with bleeding (57.5 vs. 44.9%; p=0.041). Crude ICU mortality was lower in patients receiving DrotAA than in controls (46.4 vs. 54.9%; p=0.0004); however, multivariate analysis, which adjusted for certain relevant differences, showed that DrotAA treatment was associated with higher mortality after scheduled surgery., Conclusions: These results question the way in which the drug is used in everyday clinical practice and its efficacy in a selected subgroup, and reinforce the need for a new, independent, confirmatory trial to reassess the risk-to-benefit ratio of DrotAA.

Objective: Based on the results of the PROWESS trial the European Agency for the Evaluation of Medicinal Products has recently approved drotrecogin alfa (activated) for treatment of adult patients with severe sepsis and multiple-organ failure. We report study's data on efficacy and safety in patients with multiple-organ dysfunction., Design and Setting: Randomized, double-blind, placebo-controlled, multicenter trial in 164 medical centers., Patients: 1271 patients (75.2% of the intention-to-treat population, n=1690) with multiple-organ dysfunction at study entry., Interventions: Drotrecogin alfa (activated) n=634, 24 micro g/kg per hour for 96 h or placebo ( n=637)., Results: Observed 28-day mortality was significantly lower with drug treatment than with placebo (26.5%vs. 33.9%), cardiovascular and respiratory organ dysfunction resolved more rapidly over the first 7 days, and serious bleeding events were more frequent (2.4% vs. 1.3%)., Conclusions: Treatment with drotrecogin alfa (activated) significantly reduced 28-day mortality and more quickly resolved cardiovascular and respiratory organ dysfunction. The difference in serious bleeding event rates may be clinically significant; however, the overall benefit-risk profile appears favorable.

A systemic inflammation with the release of multiple cytokines plays an important role in the pathophysiology of sepsis. During the last years, several anti-inflammatory substances have been investigated with respect to their effects on mortality in patients with sepsis. However, only the antibody fragment of the TNFalpha binding antibody afelimomab and the recombinant human activated protein C (drotrecogin alpha [activated]) were capable of improving the outcome in controlled studies with large sample sizes. The possible administration of these substances should be restricted to patients who meet the inclusion criteria of these studies. In particular, the tight time window, which usually ends 24 h after the onset of sepsis, should be taken into consideration before starting an anti-inflammatory medication. In addition to the anti-inflammatory treatment, the control of the infectious focus and an aggressive hemodynamic stabilization must not be neglected. Ibuprofen, interleukin-1 receptor antagonists and soluble TNFalpha-receptors as well as high dosages of corticosteroids and antithrombin III do not have a place in the anti-inflammatory treatment of sepsis.