Early Initiation of Drotrecogin Alfa May Improve Survival

Peggy Peck

February 27, 2004

Feb. 27, 2004 (Orlando) — Studies of activated protein C dominated this year's poster and oral sessions on sepsis at the 33rd Critical Care Congress, the annual meeting of the Society of Critical Care Medicine. The emerging theme of the studies — as exemplified by a pair of poster presentations — is that earlier treatment with drotrecogin alfa (Xigris) is associated with improved outcome.

Avelino Verceles, MD, senior fellow in critical care at Hahnemann University Hospital in Philadelphia, Pennsylvania, told Medscape that an hour-by-hour analysis of the relationship between timing of treatment and outcome "is pretty clear that earlier treatment increases survival."

Using data collected from more than 4,400 patients in five severe sepsis studies conducted prior to U.S. Food and Drug Administration approval of the drug, Jean-Louis Vincent MD, PhD, from Erasme Hospital in Brussels, Belgium, reached the same conclusion.

Dr. Verceles and colleagues reported a small, retrospective "investigator-initiated, entirely unfunded" analysis, while Dr. Vincent was lead investigator of the Extended Evaluation of Recombinant Human Protein C (ENHANCE), which was designed as a follow-up to the phase III study, recombinant human activated PROtein C [Xigris] Worldwide Evaluation in Severe Sepsis (PROWESS), both of which were funded by Xigris maker Eli Lily & Co. in Indianapolis, Indiana.

"We think our study is the first to present an hourly breakdown of results," Herbert Patrick, MD, Dr. Verceles' coauthor and an associate professor of medicine at the MCP Hahnemann University School of Medicine and director of critical care services at the Hahnemann University Hospital, told Medscape.

In the study, 24 of 29 surviving patients received activated protein C within 24 hours of onset of severe sepsis, while only 10 of the 18 patients treated more than 24 hours after onset survived.

In the Dr. Vincent and colleagues' analysis, relative risk for mortality was 0.67 when the drug was administered immediately, 0.76 for patients who received the drug at 12 hours, 0.88 for those who received it at 24 hours, and 1.0 for patients treated 35 hours after onset of sepsis.

"Early treatment is so important that we are establishing a team of [emergency department] ED and [intensive care unit] specialists so that we can arrive at the ED, make the assessment, and immediately begin treatment," Dr. Verceles said.

His analysis included data from 47 patients treated at his institution with activated protein C from March 2001 to March 2003. "The mortality rate for all patients treated with activated protein C was 38.3%, which is higher than the 24.7% mortality rate reported by PROWESS investigators," he said.

Dr. Verceles said that in addition to timing of Xigris therapy, APACHE II scores of 25 or higher was also linked to increased mortality.

Meeting cochairman J. Christopher Farmer, MD, professor of medicine, pulmonary, and critical care medicine at the Mayo Clinic in Rochester, Minnesota, cautioned against rushing treatment with activated protein C. He told Medscape that while there are early responders to the drug, there "is also a subset that are clearly late responders and we haven't exactly figured out how to differentiate these groups."

Dr. Farmer, who was not involved in either study, added that measuring "intrinsic protein C levels does not yield a uniform marker. Some people just have lower levels, and this could be a problem. We need to get a better marker for treatment."

In addition, although Dr. Farmer said he wasn't necessarily criticizing Xigris, he noted that "the FDA was not unanimous on this drug and the truth is that it squeaked by with one vote. I'm not impugning the drug, I'm just saying that it is useful in a subset of patients. Moreover, the existence of the drug does not take away in any way from the importance of [intravenous] fluids and other established treatments."

SCCM 33rd Annual Congress: Posters 453, 445. Presented Feb. 24, 2004.

Reviewed by Gary D. Vogin, MD