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ACTIVATED
PROTEIN C INEFFECTIVE IN LOW-RISK SEPSIS
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Key Point
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| Activated protein C should not be used in the treatment of patients with severe sepsis who are at low risk for death or who have undergone surgery within the 30 days prior to sepsis development. |
DENVER—The FDA mandated further study of recombinant human activated protein C (drotrecogin alfa, activated) when it approved the drug in 2001 for adults with severe sepsis and a high risk of death. That mandate led to the ADDRESS (Administration of Drotrecogin Alfa, Activated, in Early Stage Severe Sepsis) trial, which recently failed to show any mortality benefit of activated protein C in adults with sepsis who had a low risk of death.1
“The ADDRESS trial certainly needed to be done,” remarked Robert A. Balk, MD. “Although we saw in the PROWESS trial that activated protein C reduced mortality in sepsis patients at high risk for death, that trial was not adequately powered to draw conclusions about sepsis patients with a low severity of illness,” said Dr. Balk, Director of Pulmonary and Critical Care Medicine at Rush University Medical Center in Chicago.
Besides having no mortality benefit in such patients, activated protein C raised their risk of serious bleeding complications. “Both of those possibilities were probably what kept activated protein C from being the blockbuster medication that some thought it might be when the PROWESS results became available,” Dr. Balk reasoned.
EARLY TERMINATION
Enrollment in ADDRESS was discontinued earlier than planned in accordance with the data-monitoring committee’s futility guidelines. There was “less than a 5% chance of success of meeting the prospectively defined objective of a significant reduction in the risk of death from any cause [at 28 days],” explained the investigators. “The expected increase in the risk of bleeding with the use of [drotrecogin alfa] also contributed to the recommendation to terminate the trial.”
Thus, despite an original projected enrollment of approximately 11,000 participants, ADDRESS ultimately included only 2,640 adults with severe sepsis and a low risk of death, which was defined as an APACHE II score of less than 25 or as single organ failure. These patients were randomized to a 96-hour IV infusion of placebo (0.9% sodium chloride) or activated protein C at a dose of 24 µg/kg/h. “Patients had to begin treatment with the study drug within 48 hours of documentation of the first organ dysfunction,” the investigators noted.
Of the entire study population, 1,297 in the placebo group and 1,316 in the treatment group completed the trial and were included in the final analysis. There was no significant difference between groups regarding the primary end point of 28-day all-cause mortality (17% and 18.5%, respectively). “[T]he difference remained nonsignificant after adjustment for the APACHE II score before infusion of the study drug,” the investigators observed.
The treatment and placebo groups had virtually identical in-hospital mortality rates—20.6% and 20.5%, respectively.t>
In a post hoc analysis of the 635 patients who underwent surgery within 30 days prior to study enrollment and had single organ dysfunction, 28-day mortality was significantly higher for those in the activated protein C group (20.7% vs 14.1% in the placebo group). Additionally, in-hospital mortality for the two groups was 23.4% and 19.8%, respectively, in this analysis; that difference was significant as well.
The activated protein C group had a greater incidence rate of serious bleeding than did the placebo group during the 96-hour infusion (2.4% vs 1.2%) and the 28-day study period (3.9% vs 2.2%). The same was true in the post hoc analysis (10.3% vs 5.1% and 10.9% vs 6.1%).
Because of its early termination, acknowledged the investigators, the ADDRESS trial “did not enroll a sufficient number of patients to yield a precise estimate of the effect of [drotrecogin alfa] in patients with sepsis and a low risk of death.” However, they pointed out that the results were consistent with those of a post hoc subgroup analysis of the PROWESS population. “These results indicate that [drotrecogin alfa] should not be used in patients with severe sepsis who are at low risk for death,” they concluded.
LOOKING BACK AT THE FDA’S APPROVAL
In an accompanying editorial, Joseph E. Parrillo, MD, stressed that the FDA was justified in its approval of activated protein C despite concerns about the risk of substantial bleeding complications, protocol revisions influencing the PROWESS results, and patients’ APACHE II scores being difficult to determine accurately in a clinical setting.2 “The FDA argued that the protocol revisions could not account for the reduction in 28-day mortality, that APACHE II scores could be easily and rapidly determined clinically, and that the FDA-required labeling would minimize the risk of bleeding,” pointed out Dr. Parrillo, Head of Cardiovascular Disease and Critical Care Medicine at the Cooper Heart Institute in Camden, New Jersey.
“With approval of activated protein C in 2001, the FDA’s Jay Siegel wrote that the agency hoped to save lives with this therapy and to ‘gather the information necessary to refine its use further,’” Dr. Parrillo observed. “This refinement is under way.”
—Timothy Begany
References
1. Abraham E, Laterre P-F, Garg R, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005;353:1332-1341.
2. Parillo JE. Severe sepsis and therapy with activated protein C. N Engl J Med. 2005;353:1398-1400.
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