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Previous Volume 353:1332-1341 September 29, 2005 Number 13 Next

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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.

Source Information

From the Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver (E.A.); the Department of Critical Care Medicine, St. Luc University Hospital, Université Catholique de Louvain, Brussels (P.-F.L.); Lilly Research Laboratories, Eli Lilly, Indianapolis (R.G., H.L., B.L.T., N.A., B.G.U., W.L.M.); Metro Hospital and Heart Institute, Noida, Uttar Pradesh, India (D.T.); Centre Hospitalier Universitaire de Limoges, Hôpital Dupuytren, Limoges, France (B.F.); Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville (J.S.G.); the First Department of Medicine, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Mannheim, Germany (M.B.); the Adult Intensive Care Unit, Hospital de Clínicas, Universidade Federal do Paraná, Paraná, Brazil (A.R.-N.); Universitätsklinik Aachen, Aachen, Germany (R.R.); Centre Hospitalier Universitaire de Tours, Hôpital Bretonneau, Tours, France (D.P.); and Klinikum der Medizinischen Fakultät der Martin-Luther-Universität, Halle/Saale, Germany (A.S.).

Address reprint requests to Dr. Abraham at the Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262, or at edward.abraham{at}UCHSC.edu.

Full Text of this Article

Related Letters:

Drotrecogin Alfa (Activated) in Severe Sepsis
Friedrich J. O., LaRosa S. P., Baillie J.K., Murray G., Abraham E., Laterre P.-F.
Extract | Full Text | PDF  
N Engl J Med 2006; 354:94-96, Jan 5, 2006. Correspondence

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