Drotrecogin Alfa (Activated) in Severe Sepsis

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Abstract
In the article by Abraham et al. (Sept. 29 issue),1 the ADDRESS (Administration of Drotrecogin Alfa [Activated] in Early Stage Severe Sepsis) trial showed no benefit of drotrecogin alfa (activated) (DrotAA) in patients with severe sepsis and a low risk of death (defined by single-organ failure or an Acute Physiology and Chronic Health Evaluation [APACHE II] score 2 In contrast to the prematurely terminated PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial,3 the ADDRESS study showed higher mortality in its subgroup of patients treated with DrotAA who had an APACHE II score of 25 or more. When the subgroups of the two trials that had an APACHE II score of 25 or more were combined with the use of standard meta-analysis software (Review Manager, version 4.2) and a random-effects model, there was substantial heterogeneity between the two results (P=0.01; I2 =84 percent, where I denotes quantification of the degree of heterogeneity), and no significant benefit in 28-day mortality was shown (relative risk, 0.90; 95 percent confidence interval, 0.54 to 1.49) ( Figure 1 ). Likewise, combining subgroups that had multiple-organ failure did not show a major benefit. The previous discrepant results in trials of treatment for sepsis that used early-stopping rules4 or retrospective subgroups5 and had apparently even higher risks of bleeding events, including intracranial hemorrhage (e.g., in the open-label DrotAA study Extended Evaluation of Recombinant Human Activated Protein C [ENHANCE]6), suggest that another study in which a high risk of death is prospectively defined is urgently needed to determine whether DrotAA is beneficial even in this subgroup.