Web site designed and maintained by
Chris Cairns
© SICS EBM Group 2004
|
|
|
|
SEPSIS: Drotrecogin alfa (activated) long-term effect only in APACHE II ≥ 25 subgroup
Three-part Clinical Question: Patients: Critically ill patients with severe sepsis. Intervention: Whether or not to treat with activated protein C (drotrecogin alfa (activated);(DrotAA)). Outcome: Long-term survival.
The Study: PROWESS Study: a double blind RCT with intention-to-treat. Retrospective, previously unplanned, cross-sectional, blinded follow-up of patients.
PROWESS study: intial 28-day follow-up. This study: Retrospective follow-up information post day-28 on these patients. Follow-up: 100% of subjects at 28 days, 98% at hospital discharge, 94% at 3 months, and 93% at one year. To allow for subgroup analyses based on four known predictors of sepsis-associated mortality each patient’s age, APACHE II score, functional capacity and the number of their organs dysfunctioning were identified. Entry and exclusion criteria were the same as in the PROWESS study.
The Evidence:
EBM Comments:
1. Do the methods allow accurate testing of the hypothesis? No. There were important limitations to the method of this study. PROWESS as only powered to show a treatment effect at 28 days, not 1 year and beyond. Follow-up was incomplete, variable and irregular. Any sub-group analysis was post-hoc.
2. Do the statistical tests correctly test the results to allow differentiation of statistically significant results? Yes
3. Are conclusions valid in light of the results?The study observed that subjects treated with APC had higher survival at hospital discharge but there was no statistical difference between treatment arms in duration of survival or differences in survival rates at time points after hospital discharge. However, in post-hoc sub-group analysis, there was a highly significant survival benefit with therapy in subjects with higher APACHE II (≥25) scores but no evidence of benefit in subjects with lower APACHE II scores.In view of the above limitations the study urged caution in the interpretation of survival benefit based on APACHE II scoring however concluded that the current FDA recommendation to restrict the use of APC to sicker patients is supported.
4. Did results get omitted, and why? 83 patients alive at the end of PROWESS were lost to follow up (7.6%). Subjects lost to follow-up were not different in baseline characteristics.
5. Did they suggest areas of further research? This study shows long-term follow up in multi-centre ICU trials is possible. Sample size calculations in future large ICU trials should include 1-year survival as an end-point.
6. Did they make any recommendations based on the results and were they appropriate? Supports limitation of drotrecogin alfa (activated) use to those with APACHE II ≥ 25.
7. Is this study relevant to my clinical practice? Yes, but the methodolology means we give it less weight. The NICE guidance recommends drotrecogin alfa (activated) when there is severe sepsis with 2 organ failure. The NICE guideline needs updating in the light of this study and that of the, as yet unpublished, ADDRESS study.
8. What level of evidence does this study represent? 1-: Although this is a cohort follow up study, the treatment groups the patients were assigned to in the original study were randomised. Method of group allocation remains the primary determinant in studies looking at treatment effect. The follow up loss, secondary trial added on to a primary one justify the “-“ rating.
9. What grade of recommendation can I make on this result alone? N/A
10. What grade of recommendation can I make when this study is considered along with other available evidence? B: Original PROWESS study ranked 1+, so B recommendation that APC improves 28 day mortality.
11. Should I change my practice because of these results? Not at present whilst awaiting the results of further prospective trials. APC is still merited in the management of the patient with severe sepsis or septic shock who has developed multiple organ failure despite best standard care.
12. Should I audit my current practise because of these results? No.
Appraised by: Dr Caroline Hawe, Stirling Royal
Infirmary; Thursday, May 05, 2005
Edited by CC & MD.
Citation: EBM Critical Appraisals. Scottish Intensive Care Society EBM Group. Hawe C. 2004 : Derek C Angus, et al. The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis. Crit Care Med 2004;Vol 32; No 11: 2199-22
©SICS EBM 2005
| ||||||||||||||||||||||||||||||||||||||||||
