Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.
This review may be edited
Posted By: Gordon S Doig
Posted Date: 20 Sep 2007
Title: Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.
Authors: Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, François B, Guy JS, Brückmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL; Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group.
Reference: N Engl J Med. 2005 Sep 29;353(13):1332-41
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Abstract: Background In November 2001, the Food and Drug Administration (FDA) approved drotrecogin alfa (activated) (DrotAA) for adults who had severe sepsis and a high risk of death. The FDA required a study to evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death.
Methods We randomly assigned adult patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score <25 or single-organ failure) to receive an intravenous infusion of placebo or DrotAA (24 µg per kilogram of body weight per hour) for 96 hours in a double-blind, placebo-controlled, multicenter trial. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. In-hospital mortality within 90 days after the start of the infusion was measured, and safety information was collected.
Results Enrollment in the trial was terminated early because of a low likelihood of meeting the prospectively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA. The study enrolled 2640 patients and collected data on 2613 (1297 in the placebo group and 1316 in the DrotAA group) at the 28-day follow-up. There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality (17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group; P=0.34; relative risk, 1.08; 95 percent confidence interval, 0.92 to 1.28) or in in-hospital mortality (20.5 percent vs. 20.6 percent; P=0.98; relative risk, 1.00; 95 percent confidence interval, 0.86 to 1.16). The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion (2.4 percent vs. 1.2 percent, P=0.02) and the 28-day study period (3.9 percent vs. 2.2 percent, P=0.01).
Conclusions The absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications, indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
Unsure. Although we are reasonably certain that this trial was centrally randomised, the authors do not explcitly state this.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
Yes. The authors report minimal loss to follow up and withdrawal of consent by study arm.
2b. Were patients analyzed in the groups to which they were randomized?
3. Were patients, health workers, and study personnel blind to treatment?
Yes. The study was blinded by placebo infusion.
4. Were the groups similar at the start of the trial?
Yes. The authors report minimal baseline imbalance.
5. Aside from the experimental intervention, were the groups treated equally?
Unsure. The authors do not report major concommitent interventions.
What are the Results?
1. How large was the treatment effect?
The study was stopped early due to 'futility'.
There was no significant difference in the primary outcome of 28 day mortality of 17% in placebo and 18.5% DrotAA (absolute risk difference 1.5, 95%CI -1 to 4%, p=0.33).
2. How precise was the estimate of the treatment effect?
See 95% CI above.
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
No. This is a negative underpowered trial. It was originally calculated that 11,400 patients would be required to be 90% certain of detecting a 2% difference in treatment. Due to early stopping, this trial cannot rule out the presence of a meaningful treatment difference between the two groups.
2. Were all clinically important outcomes considered?
Yes. Day 28 mortality plus hospital discharge mortality up to day 90. 1 year follow-up is to be published seperately.
3. Are the likely treatment benefits worth the potential harms and costs?

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Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.

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