Drug not beneficial for patients with severe sepsis
A new study indicates that drotrecogin alfa (activated) (Xigris) has little benefit for patients with severe sepsis and a low risk of death.
Researchers terminated the Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) trial early because of the lack of perceived benefit from the drug and an increased incidence of serious bleeding complications. Drotrecogin alfa (activated) (DrotAA) had been approved in November 2001 for adults who had severe sepsis and a high risk of death. As a condition of approval, the FDA required Eli Lilly, manufacturer of the drug, to test it in patients with severe sepsis and a low risk of death. The results of the ensuing double-blind, randomized, placebo-controlled Phase IV trial were published in the Sept. 29 issue of the New England Journal of Medicine.
Patients, enrolled in the trial between September 2002 and February 2004, were considered eligible if they had severe sepsis — defined as the presence of a suspected or known infection and sepsis-induced dysfunction of at least one organ, and a low risk of death. A low risk of death was defined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score of less than 25 or single-organ failure.
Patients were randomly assigned to receive a 96-hour intravenous infusion of placebo or DrotAA at a dose of 24 µg per kilogram of body weight per hour. There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality (17% in the placebo group vs. 18.5% in the DrotAA group) or in in-hospital mortality (20.5% vs. 20.6%).
The study was originally designed to enroll more than 11,000 patients. Only 2,640 patients, however, had enrolled in the study when it was terminated. The data-monitoring committee recommended stopping the trial because there was a less than 5% chance of meeting its defined goal of a "significant reduction in the risk of death from any cause," assessed 28 days after the initiation of the infusion of DrotAA.
The increase in the risk of bleeding with the use of the drug also contributed to this decision. The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion (2.4% vs. 1.2%) and the 28-day study period (3.9% vs. 2.2%). The researchers say that in both treatment groups, about one-third of the serious bleeding events were related to a procedure during the infusion period.
Because of the results, the researchers advise 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. An editorial that accompanied the trial results agrees. "The ADDRESS trial confirms the lack of efficacy in patients with APACHE II scores of less than 25," wrote Joseph E. Parrillo, MD, director of the Cooper Heart Institute and professor of medicine at University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School in Camden.
Two other studies, one pediatric, also warn of an increased bleeding risk with DrotAA, he continues. They "confirm that bleeding is a significant risk with activated protein C, and clinicians must carefully exclude patients who have a high likelihood of bleeding," he says.
A new study indicates that drotrecogin alfa (activated) (Xigris) has little benefit for patients with severe sepsis and a low risk of death.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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