Drotrecogin Alfa (Activated) for Adults with Severe Sepsis and a Low Risk of Death

Abstract

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.

A summary of the Japan septic disseminated intravascular coagulation study

“…Over the past few decades, although some anticoagulant agents, such as antithrombin (AT), tissue factor pathway inhibitor, and activated protein C, have been investigated for use in patients by international large randomized controlled trials (RCTs), no remarkable effect on the mortality rate has been reported 4, 5, 6, 7. However, the post‐hoc subgroup analyses of those RCTs indicated that the anticoagulant therapies resulted in improved mortality rates in patients with sepsis‐induced DIC 8, 9.…”

Evidence‐based sepsis therapy: A hospitalist perspective

“…Although this effect was of borderline significance in PROWESS (3.5% vs. 2% in the placebo group, P ϭ .06), 29 it was confirmed in subsequent trials (3.9% vs. 2.2%, P ϭ .01) 30 and may be larger still in open-label use, at 6.5%. 17,31 Intracerebral hemorrhage (ICH), a particularly devastating complication, occurred in 0.2% of the PROWESS patients and 0.5% of patients in 2 subsequent studies 30,32 ; in both major trials, there was a single extra event in the APC arm. 29,30 Like serious bleeding in general, ICH was more common in open-label use, occurring in 1.5% of patients.…”

“…32,35 The ADDRESS trial also failed to demonstrate a benefit in a subgroup of patients with APACHE II scores above 24, although it was underpowered to do so, and according to enrollment criteria, none of those patients had multiorgan failure. 30 However, in the subgroup of PROWESS patients with APACHE II scores greater than 24, the absolute reduction in mortality was a full 13%, 17 with a corresponding NNT of 7.7, and although the PROWESS findings have not been duplicated in a second randomized trial, a single-arm, open-label study of APC (ENHANCE) showed a nearly identical mortality rate. 31 Pending confirmatory trials, APC remains a recommended therapy for selected patients sick enough to benefit and without excessive bleeding risk.…”

“…17,31 Intracerebral hemorrhage (ICH), a particularly devastating complication, occurred in 0.2% of the PROWESS patients and 0.5% of patients in 2 subsequent studies 30,32 ; in both major trials, there was a single extra event in the APC arm. 29,30 Like serious bleeding in general, ICH was more common in open-label use, occurring in 1.5% of patients. 31,33 Therefore, it is vital to have strict adherence to exclusion criteria and familiarity with the risk factors for serious bleeding.…”

“…34 A subsequent study, ADDRESS, confirmed there was no benefit to septic patients with a low risk of death. 30 In the ADDRESS study 2613 patients with severe sepsis and either an APACHE II score less than 25 or single organ failure were randomized to APC or placebo. No differences were found in 28-day and in-hospital mortality; among patients who had undergone surgery in the previous 30 days, those receiving APC had a significantly increased risk of death (20.7% vs. 14.1%, P ϭ .03).…”