27 Jul 09

Early drotrecogin alpha (activated) administration in severe sepsis is associated with lower mortality: a retrospective analysis of the Canadian ENHANCE cohort

Posted in rhAPC, Sepsis at 11:06 by Laci

By R Hodder, R Hall, J Russell, H Fisher and B Lee

Critical Care 2009, 13:R78

Early multimodal treatment of severe sepsis, including the use of drotrecogin alfa (activated) (DrotAA) when indicated, is considered essential for optimum outcome. However, predicting which infected patients will progress to severe sepsis and the need for aggressive intervention continues to be problematic. We therefore wished to explore whether there were any potential early markers that might predict improved survival in response to early use of DrotAA in patients with severe sepsis. In particular, in the dynamic setting of severe sepsis, we postulated that changes in markers reflecting evolving rather than baseline clinical status might guide therapy.

Methods
Data on a cohort of 305 Canadian patients from the open label ENHANCE trial of DrotAA in severe sepsis was retrospectively analyzed to search for potential clinical predictors of outcome in severe sepsis. Patients received a 96-hour infusion of DrotAA and were followed for 28 days. The association between time to treatment and mortality within subgroups defined by dynamic changes in various potential markers was explored.

Results
Mortality at 28 days was 22.6% and the variables of age, time to treatment, and early changes in serum creatinine and platelet count were identified by logistic regression as independent predictors of mortality. Across all age ranges, 28-day mortality was lower when DrotAA was administered within 24 hours of first sepsis-induced organ dysfunction compared to administration after 24 hours for both subgroups of patients defined by changes in platelet count and creatinine within the first day.

Conclusions
These findings suggest that when indicated, treatment with DrotAA should be initiated as soon as possible, regardless of age.

03 Jan 09

Filter survival time and blood products requirement in patients with severe sepsis receiving drotrecogin alfa (activated) and requiring renal replacement therapy

Posted in Acute Kidney Injury/RRT, rhAPC at 0:51 by Laci

By L Camporota, E Corno, E Menaldo, J Smith, K Lei, R Beale and D Wyncoll

Critical Care 2008;12:R163

Drotrecogin alfa (activated) (DrotAA) is licensed for the treatment of severe sepsis with multiple organ failure. Patients with severe sepsis on renal replacement therapy (RRT), who typically receive additional anticoagulation to prevent circuit clotting, may be at higher risk of bleeding when DrotAA is administered in addition to standard anticoagulation. However, the effects of DrotAA on filter duration in the absence of additional anticoagulation are not established. The aim of this study was to analyse the filter survival time (FST), and to quantify the requirement of packed red cells (PRC) and blood products during DrotAA infusion.

Methods
This was a single-centre, retrospective observational study conducted in an adult intensive care unit (ICU). Thirty-five patients with severe sepsis who had received both RRT and DrotAA were identified, and all relevant clinical and laboratory data were retrieved from the departmental electronic patient record. We compared haemofilter parameters, blood products requirement and haemodynamic data recorded during RRT and the infusion of DrotAA with those recorded on RRT with standard anticoagulation after the DrotAA infusion had been completed (post-DrotAA).

Results
The proportion of filter changes due to filter clotting was similar during DrotAA infusion and with conventional anticoagulation post-DrotAA infusion. There was no difference in the FST and filter parameters during DrotAA in the presence or absence of additional anticoagulation with heparin or epoprostenol. A similar proportion of patients required red cell transfusion, although a greater proportion of patients received platelet and fresh frozen plasma (FFP) during DrotAA infusion compared to the post-DrotAA period with no difference between medical and surgical patients.

Conclusions
Additional anticoagulation during DrotAA infusion does not appear to improve FST. The use of DrotAA in patients with severe sepsis requiring RRT is safe and is not associated with an increased need for PRC transfusion or major bleeding events.

26 Nov 08

Influence of enrollment sequence effect on observed outcomes in the ADDRESS and PROWESS studies of drotrecogin alfa (activated) in patients with severe sepsis

Posted in rhAPC at 0:00 by Laci

By P-F Laterre, WL Macias, J Janes, MD Williams, DR Nelson, A RJ Girbes, J-F Dhainaut and E Abraham

Critical Care 2008;12:R117

We performed a study to determine whether an enrollment sequence effect noted in the PROWESS (recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis) trial exists in the ADDRESS (Administration of Drotrecogin Alfa [Activated] [DrotAA] in Early Stage Severe Sepsis) trial.

Methods
We evaluated prospectively defined subgroups from two large phase 3 clinical trials: ADDRESS, which included 516 sites in 34 countries, and PROWESS, which included 164 sites in 11 countries. ADDRESS consisted of patients with severe sepsis at low risk of death not indicated for treatment with DrotAA. PROWESS consisted of patients with severe sepsis with one or more organ dysfunctions. DrotAA (24 μg/kg per hour) or placebo was infused for 96 hours.

Results
In ADDRESS and PROWESS, there was a statistically significant interaction between the DrotAA treatment effect and the sequence in which patients were enrolled. In both trials, higher mortality was associated with DrotAA use in the subgroup of patients enrolled first at study sites. Compared with placebo, PROWESS mortality was lower with DrotAA treatment for the second and subsequent patients enrolled, whereas in ADDRESS, mortality remained higher for the second patient enrolled but thereafter was lower for DrotAA-treated patients. Comparison of patients enrolled first with subsequent patients enrolled indicated that the characteristics of patients changed. Subsequently enrolled patients were treated earlier, were less likely to suffer nonserious bleeds (ADDRESS), and experienced fewer protocol violations (PROWESS).

Conclusions
Analyses suggest that an enrollment sequence effect was present in the ADDRESS and PROWESS trials. Analysis of this effect on outcomes suggests that it is most apparent in patients at lower risk of death. In PROWESS, this effect appeared to be associated with a reduction of the DrotAA treatment effect for the first patients enrolled at each site. In ADDRESS, this effect may have contributed to early termination of the study. The finding of an enrollment sequence effect in two separate trials suggests that trial designs, site selection and training, data collection and monitoring, and statistical analysis plans may need to be adjusted for these potentially confounding events.

19 Jul 08

A retrospective observational study of drotrecogin alfa (activated) in adults with severe sepsis: Comparison with a controlled clinical trial

Posted in rhAPC, Sepsis at 19:34 by Laci

By A Wheeler, J Steingrub, G A Schmidt, P Sanchez, J Jacobi, W Linde-Zwirble, B Bates, R L Qualy, B  Woodward, M Zeckel

Crit Care Med 2008;36:14-23

To compare characteristics and outcomes of patients treated with drotrecogin alfa (activated) (DrotAA) in clinical practice to those treated in a phase III randomized controlled trial (PROWESS).

Design
Observational data were collected retrospectively from patients who received DrotAA as part of physician-directed treatment.

Setting
Intensive care units of five teaching institutions.

Patients
Patients were =18 yrs old, had severe sepsis (confirmed/suspected infection with one or more sepsis-induced organ dysfunctions), and received DrotAA.

Interventions
None.

Measurements and Main Results
Baseline demographics, severity of illness, time from organ dysfunction onset to DrotAA treatment, daily assessment of organ dysfunction, serious bleeding events, and in-hospital mortality were reported. Timing from severe sepsis documentation to start of DrotAA infusion was categorized: day 0 (same calendar day); day 1 (next calendar day); and day =2 (second calendar day or later). Clinical practice patients (n = 274) were younger, had more comorbidities, had higher severity of illness (as measured by organ dysfunction or greater vasopressor/ventilator use), and received DrotAA later than PROWESS patients (all p < .05). Overall hospital mortality for clinical practice patients was 42%, compared with 37% for DrotAA-treated PROWESS patients with Acute Physiology and Chronic Health Evaluation II score =25. Mortality for day 0, day 1, and day =2 groups was 33%, 40%, and 52%, respectively. In PROWESS, the vast majority were treated on day 0 or day 1. Serious bleeding events during infusion were noted in 4.0% of clinical practice patients compared with 2.2% of PROWESS DrotAA-treated patients with Acute Physiology and Chronic Health Evaluation II score =25.

Conclusions
Patients treated in clinical practice differed from those in PROWESS. Patients were younger, had more comorbidities, had greater severity of illness, and had longer mean time from severe sepsis onset to the start of DrotAA. Hospital mortality for patients treated within 1 day of severe sepsis onset was similar to DrotAA-treated PROWESS patients. While the low number of serious bleeding events precludes a definitive assessment, the observed incidence of serious bleeding events in clinical practice patients was numerically higher than in DrotAA-treated PROWESS patients.

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