Drotrecogin Alfa (Activated)

Abstract

Drotrecogin alfa (activated), recombinant human activated protein C, inhibits coagulation and inflammation and promotes fibrinolysis in patients with severe sepsis. 850 patients with severe sepsis treated with intravenous drotrecogin alfa (activated) 24 microg/kg/h for 96 hours had a significantly greater reduction in 28-day all-cause mortality (24.7%) than 840 placebo recipients (30.8%) in a randomised, double-blind, placebo-controlled study. The drug was associated with a 19.4% reduction in the relative risk of death at 28 days compared with placebo. Baseline characteristics of and pre-existing conditions in patients with sepsis appeared to have no effect on the efficacy of drotrecogin alfa (activated). A significantly greater reduction in median percentage change from baseline plasma D-dimer levels (a coagulation marker) was seen with drotrecogin alfa (activated) treatment than with placebo on study days 1 to 7 in patients with severe sepsis. On study days 1, 4, 5, 6 and 7, a significantly greater median reduction in interleukin-6 levels (an inflammation marker) from baseline was seen with drotrecogin alfa (activated) treatment than placebo. Drotrecogin alfa (activated) was associated with an increased incidence of serious bleeding events during the infusion period [2.4% vs 1.0% with placebo; p = 0.024] and the 28-day study period (3.5 vs 2.0%; p = 0.06) of the efficacy trial. This increase was primarily related to procedure-related events; there were no significant differences between the treatment groups in nonprocedure-related serious bleeding events. The most frequent site of bleeding was the gastrointestinal tract. With the exception of bleeding events, there were no clinically significant differences between treatment groups in the efficacy trial in the incidence of adverse events. Of the 210 deaths in patients with severe sepsis treated with drotrecogin alfa (activated) 24 microg/kg/h in the efficacy trial, four deaths due to haemorrhage and one due to cerebral oedema were possibly related to the study drug.

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“…Recombinant human activated protein C (APC) is known to inhibit coagulation and inflammation, and to promote fibrinolysis in patients with severe sepsis [13]. Binding of APC to the endothelial cell protein C receptor results in a number of actions, including increased activity of APC itself and inhibition of both NF-κB and apoptosis [14].…”

Effect of Drotrecogin alfa (activated) on platelet receptor expressionin vitro

“…The median plasma concentration of exogenous administrated APC at steady state is 0.045 mg mL À1 [9]. A previous study revealed an APC-dependent reduction of CD62P on platelet surface exclusively after activation with recombinant tissue factor [10].…”

Progress in the Management of Sepsis: The Surviving Sepsis Campaign

“…Currently available strategies for the management of sepsis patients include: timely patient identification and diagnosis [15]; rapid identification of causative organisms; appropriate, timely antimicrobial therapy [4,14,16,17]; improved ventilatory techniques (lowpressure ventilation) [18,19]; appropriate (goal-directed) hemodynamic support [20]; targeted pharmacological therapies (drotrecogin alfa [activated]) [16], glucocorticoid therapy [21]; glycemic control (intensive insulin therapy) [22,23]; appropriate nutrition [16]; effective supportive therapies [24] (prophylaxis against stress ulcers, administration of anticoagulants, dialysis [25,26]); and patient management by highly qualified clinicians and nursing staff [4,14,16,17,19]. These strategies have helped to reduce the incidence of infections, support failing organs and prevent complications [20].…”