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Early use of drotrecogin has benefits in severe sepsis

Reuters Health • The Doctor's Channel Daily Newscast

NEW YORK (Reuters Health) – In patients with severe sepsis, early rather than later treatment with drotrecogin alfa (activated), in conjunction with other recommended therapies, may improve survival, results of an exploratory retrospective analysis of the Canadian ENHANCE cohort confirm.

This analysis, the authors explain in their report posted online May 20 in the journal Critical Care, suggests that, “when indicated, treatment with drotrecogin alfa should be initiated as soon as possible, regardless of age.”

Drotrecogin alfa — a recombinant form of the endogenous regulator of coagulation and inflammation, activated protein C — is recommended as part of a “sepsis bundle” together with an early goal-directed approach to resuscitation, the study team notes.

The ENHANCE (Extended Evaluation of Recombinant Human Activated Protein C) study, an open label study of drotrecogin alfa in 2378 patients with severe sepsis, showed that administration of the drug within 24 hours of first organ failure was significantly associated with lower mortality.

In the new analysis, Dr. Richard V. Hodder of Ottawa Hospital, Ontario and colleagues explored whether, in the dynamic setting of severe sepsis, there were any potential early markers reflecting evolving rather than baseline clinical status that might help guide therapy with drotrecogin alfa.

Their analysis centered on 305 patients who received a 96-hour infusion of drotrecogin alfa; 141 patients received the drug within the first 24 hours and 164 received it after 24 hours.

The mortality rate at 28 days was 22.6% and, according to the investigators, the variables of age, first day change in serum creatinine and platelet count, and time to treatment emerged as independent predictors of mortality.

Patients aged 49 and younger had a lower odds of mortality than patients aged 65 and older (odds ratio, 0.25 to 0.27), Dr. Hodder and colleagues found. A rise in serum creatinine of 50 µmol/L on day 1 increased the odds of death by 32%, whereas an increase in platelet count of 50 billion/L on day 1 decreased the odds of mortality by 34%.

“Across all age ranges, 28-day mortality was lower when drotrecogin alfa was administered within 24 hours of first sepsis-induced organ dysfunction compared to administration after 24 hours for both subgroups of patients defined by changes in platelet count and creatinine within the first day,” the investigators report.

The risk of mortality based increased by 23% with each six-hour delay in receiving drotrecogin alfa, they further note.

“Waiting until clear signs of clinical deterioration are present before initiating treatments for severe sepsis may represent a lost opportunity for improvement and confer a worse prognosis,” Dr. Hodder and colleagues conclude.

Mirroring past studies, bleeding was the only serious side effect of drotrecogin treatment.

Critical Care 2009;13.