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SEPSIS: aPC doesn’t reduce mortality in low risk patients
Citation/s:
Abraham E, et al. Drotrecogin Alfa (Activated) for adults with severe sepsis and
a low risk of death. New Engl J Med 2005;353:1332-41
Three-part Clinical Question: Patients: Severe sepsis (presence of a suspected or a known infection and sepsis-induced dysfunction of at least one organ) with a low risk of death (APACHE <25) Intervention: aPC for 96hrs (24mcg/kg/hr) compared with placebo (N Saline) Outcome: Primary – 28 day
mortality, secondary – hospital mortality, adverse events. Search Terms: sepsis, treatment, outcome, APC
The Study: Double-blinded RCT
with concealed allocation and intention-to-treat. The Study Patients: Included:
see above. Excluded: aPC indicated (varied dependant on country - but for
example; sepsis with multi-organ failure and a high risk of death, for example
APACHE ³25) or contraindicated;
increased risk of bleeding, moribund, uncorrectable disease, no commitment to
aggressive management. If patient’s disease progressed and the investigator
thought aPC was in the patient’s best interests, treatment was unblinded and
study drug discontinued. Patients still followed-up. Control group (N = 1307; 1297
analysed): Standard care with placebo. Experimental group (N = 1333; 1316 analysed): Standard care with APC
The Evidence:
All patients:
EBM Comments: 1. Do the methods allow accurate testing of the hypothesis? Yes. The study was terminated early after interim analyses (in protocol and an FDA requirement) on grounds of futility (Less than 5% chance of meeting the prospectively defined objective of a significant reduction in death.). 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? Yes. Although the trial was stopped early this was on pre-defined criteria of futility as there was no benefit from aPC in patients with severe sepsis and a low risk of death. 4. Did results get omitted, and why? Yes. 9 patients lost to follow-up. 18 withdrew consent. This represents only 1% of enrolled patients however and is not likely to affect overall result. 5. Did they suggest areas of further research? No. 6. Did they make any recommendations based on the results and were they appropriate? Yes – as Q3. Drotrecogin alfa should not be used in patients with severe sepsis who are at low risk of death, such as those with single-organ failure or an APACHE II score <25. 7. Is the study relevant to my clinical practice? Yes 8. What level of evidence does this study represent? 1++ 9. What grade of recommendation can I make on this result alone? A 10. What grade of recommendation can I make when this study is considered along with other available evidence? A, findings support the previous post-hoc analyses of PROWESS study data. Sub-group analyses done in different ways have delivered a consistent message. 11. Should I change my practice because of these results? Yes. If you are currently using aPC in this ‘low risk’ patient population. If you are following European license and NICE guidelines (which require multiple organ failure) there may be few patients in this category. You may wish to consider using APACHE II score ≥25 as an additional filter. 12. Should I audit my current practice because of these results? Yes , there is a need to monitor indications and outcome with this drug.
Appraised by: Dr Paul Harrison & Dr
Chris Cairns, Stirling Royal Infirmary, UK ; 29 September 2005 Citation: EBM Critical Appraisals. Scottish Intensive Care Society EBM Group. Harrison P, Cairns CJS. 2005 : Abraham E, et al. Drotrecogin Alfa (Activated) for adults with severe sepsis and a low risk of death. New Engl J Med 2005;353:1332-41. Reviewed & edited by BC & MD Kill or Update By: October 2010
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