Drotrecogin alfa, a biologic agent used to treat adults with severe sepsis who are at high risk of death, may not be appropriate for patients with single organ dysfunction and recent surgery, and should be administered only after careful consideration of the potential risks and benefits, according to a new warning by Eli Lilly & Co., which manufactures the drug.
Lilly added the warning to the prescribing information after two studies indicated a small but clinically important increase in the rate of all-cause mortality among these patients treated with the agent, compared with those who received placebo. Physicians and other health care providers received a letter in February alerting them to the new warning.
Drotrecogin alfa (Xigris) is indicated only for adult patients with severe sepsis who are at high risk of death. The subset of patients with single organ dysfunction and recent surgery, “may not be at high risk of death, and therefore may not be indicated for Xigris,” the warning states.
The warning was based on a preliminary analysis of the Administration of Drotrecogin Alfa [Activated] Early Stage Severe Sepsis (ADDRESS) randomized, placebo-controlled trial and a reanalysis of Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS), the drug's phase III registration trial. In the PROWESS trial of almost 1,700 patients, only 98 had single organ dysfunction and recent surgery (within 30 days of therapy). Among the 49 treated patients, 10 died within 28 days of treatment and 14 were hospitalized; among the patients treated with placebo, eight died within 28 days and eight were hospitalized.
The ADDRESS trial studied the drug's effect in patients who were less critically ill (Acute Physiology and Chronic Health Evaluation [APACHE] II score less than 25, or single sepsis-induced organ failure at any APACHE II score). Among 323 treated patients, 67 died within 28 days and 76 were hospitalized; among the placebo-treated patients, 44 died within 28 days and 62 were hospitalized.
“The important thing to note is that this is a preliminary finding,” said Carole Puls, spokesperson for Lilly. “We issued the warning because we felt these patients may not be at high risk for death and so the drug is not indicated for them.”
During Food and Drug Administration approval hearings for drotrecogin alfa, members of the Anti-Infective Drugs Advisory Committee noted that the drug was less effective in reducing mortality in patients with less severe sepsis, who had a better prognosis.
The main safety concern during the hearings was serious bleeding events, which the company said appeared to be associated with vessel trauma or severe coagulopathy and were consistent with the product's antithrombotic and profibrinolytic effects. Serious bleeding adverse events occurred in 3.5% of those on drotrecogin alfa, compared with 2% of those on placebo. Of the serious bleeding events among those on drotrecogin alfa, most occurred during or immediately after the patients received the infusion. Bleeding sites were gastrointestinal, intraabdominal, intrathoracic, retroperitoneal, intracranial, genitourinary, and skin/soft tissue.
Drotrecogin alfa is a genetically engineered version of human activated protein C. This molecule is a naturally occurring protein that, when activated, promotes fibrinolysis, inhibits thrombosis and inflammation, and is an important modulator of the coagulation and inflammation associated with severe sepsis, according to Lilly. Evidence suggests that the process that activates the molecule may be impaired by sepsis, and therefore, septic patients have low levels of activated protein C.