Several drugs given as adjuvant therapy to reduce mortality in patients with sepsis have proved unsuccessful so far. Now a large clinical trial has found that administration of recombinant human activated protein C—or drotrecogin alfa activated—leads to a significant reduction in mortality among patients with severe sepsis.
"Our results indicate that in this population, one additional life would be saved for every 16 patients treated with drotrecogin alfa activated" wrote Gordon Bernard, Vanderbilt University School of Medicine, Nashville, and colleagues (New England Journal of Medicine 2001;344:699-709).
Despite intensive medical care, antibiotic treatment, and surgery when indicated, mortality in patients with sepsis remains as high as 30-50%. The acute organ dysfunction observed in severe sepsis is known to be the consequence of generalised inflammatory and procoagulant host responses to infection.
Activated protein C—a component of the natural anticoagulant system—is a serine protease with substantial anti-inflammatory, antithrombotic and profibrinolytic properties. In this randomised, double blind, multicentre trial conducted in 11 countries, 1690 eligible patients with severe sepsis were given intravenous activated protein C (24 m g/kg per hour) or placebo for 96 hours. Exclusion criteria included age under 18 years and a higher risk of bleeding.
After 28 days of follow up or until death, 259 of 840 patients in the placebo group (30.8%) and 210 of 850 in the treatment group (24.7%) had died. This represented a 19.4% reduction in the relative risk of death and a 6.1% absolute reduction in the risk of death (P=0.005) associated with this treatment.
A survival benefit was evident throughout the 28 day study period, and the treatment was effective regardless of age, disease severity, number of dysfunctional organs, site of infection, and type of micro-organism. Treatment was associated with a reduction in both plasma d-dimer levels (indicating that the procoagulant effects of sepsis were lowered by this treatment) and serum levels of interleukin 6 (indicating that the agent attenuated the inflammatory cascade).
Consistent with the antithrombotic activity of the drug was that bleeding was the most common adverse event resulting from its administration, yet it occurred predominantly in patients with a predisposition to bleeding.
In an editorial in the same issue of the New England Journal of Medicine (pp 759-62) Dr Michael Matthay of the University of California, San Francisco, said that the drug "should be given to patients who meet all the inclusion criteria, including evidence of end-organ dysfunction with shock, acidosis, oliguria, or hypoxemia." It should not be given to "patients with clinical signs of mild-to-moderate sepsis who do not have evidence of end-organ injury, unless a future trial shows a clear benefit in these patients."
