February 7, 2012 (Houston, Texas) — A drug that was taken off the market in October 2011 because it failed to significantly reduce 28-day mortality in patients with septic shock demonstrated just the opposite effect in a new study, presented here at the Society of Critical Care Medicine 41st Critical Care Congress.
In a retrospective multicenter propensity-matched cohort study of 930 patients with septic shock, researchers, led by Emily Rimmer, MD, from the University of Manitoba, Winnipeg, Canada, observed a 7% absolute reduction in 30-day mortality associated with the use of recombinant human activated protein C (rhAPC).
The study was conducted at 28 academic and community intensive care units. Researchers reviewed the use of rhAPC over a 10-year period, from 1997 to 2007. Patients were randomized in a 2:1 fashion to either a control group or rhAPC.
The mortality rate was 34.5% among the 310 patients in the rhAPC group, and 41.5% among the 620 patients in the control group. The hazard ratio (HR) was 0.80 (95% confidence interval, 0.64 to 1.00; P = .05), Dr. Rimmer reported.
Patients with the lowest APACHE II scores appeared to derive the greatest benefit from rhAPC. For patients in the lowest APACHE II quartile (APACHE II, 5 to 19), the mortality rate was 9.5% in the rhAPC group and 22% in the control group (HR, 0.4; P = .04).
For patients in the remaining APACHE II quartiles, consistent reductions in mortality were seen in the rhAPC group, although they were not significant, Dr. Rimmer said.
The researchers also found that the risk for death decreased 5% per year from 1997 to 2007.
"This could be due to better care for these patients, including timely administration of antibiotics," Dr. Rimmer suggested.
Disappointing Results from PROWESS-STROKE
On October 25, 2011, Eli Lilly announced it was pulling the plug on its rhAPC drug (drotrecogin alfa, Xigris) after the postmarketing PROWESS-STROKE trial failed to show a statistically significant reduction in 28-day all-cause mortality in patients with septic shock.
In that trial of nearly 1700 septic shock patients, 26.4% of those in the drotrecogin alfa group died, as did 24.2% in the placebo group. However, there was no excess risk of bleeding with drotrecogin alfa.
At the time, Lilly's senior vice president and chief medical officer, Timothy Garnett, MD, said in a statement: "We believe the original [drotrecogin alfa] approval was appropriate and these recent results were quite unexpected. A contributing factor to these study results could be advances in the standard of care for treating severe sepsis over the past 10 years."
Drotrecogin alfa was approved by the US Food and Drug Administration (FDA) in 2001.
Dr. Rimmer said she had started the study before the drug was pulled from the market.
"We had a large database of people and thought this was a clinically important question to look at. Even though it has been withdrawn from the market, I think we added some very important information regarding time to antibiotic use and the mortality rates of sepsis," she said in an interview after her talk.
Senior author of the study, Ryan Zarychanski, MD, also from the University of Manitoba, added that this study adds to the controversy about a continued rhAPC program after the PROWESS-STROKE trial.
"This large multinational follow-up randomized controlled trial showed that [activated protein C] was of no value, and then the company pulled it off the market, but I don't think the story is that simple," Dr. Zarychanski said.
"The drug may have added value — it may still have added value — but the actual benefit of the drug may have changed over time because of changes in the way that we care for septic shock patients," he said.
Other anticoagulants are going to be studied in the intensive care unit; it behooves researchers to learn as much as possible from the activated protein C studies, Dr. Zarychanski noted.
"The potential effectiveness of future agents might change based on the standard of care patients are given. That's one of the things that we've learned from this retrospective study. Future anticoagulant trials should keep that in mind. They will have to target a group of patients who are sufficiently sick, but also sufficiently salvageable if they receive a certain care, and then ask whether the new agent will add anything to their survival," he explained.
Douglas Fish, MD, from the University of Colorado, Denver, told Medscape Medical News that the removal of the drug from the market created some controversy.
"There were a lot of people who were not big fans of the drug to begin with, and they said 'I told you so,' but there were others who had had fairly good clinical success with the drug, and the perception was that it had a clinical role," said Dr. Fish, who moderated the oral session.
"I think the reason this abstract was chosen to be presented here at an oral session was because the results are interesting, and they are counter to those in the PROWESS trial that led to the FDA removal. But I'm not sure anything will come of it," he said.
Dr. Rimmer, Dr. Zarychanski, and Dr. Fish have disclosed no relevant financial relationships.
Society of Critical Care Medicine (SCCM) 41st Critical Care Congress: Abstract 39. Presented February 5, 2012.
Medscape Medical News © 2012 WebMD, LLC
Send comments and news tips to firstname.lastname@example.org.
Cite this: Activated Protein C May Reduce Septic Shock Mortality - Medscape - Feb 07, 2012.