No More Xigris®
By Stan Deresinski, MD, FACP, FIDSA, Clinical Professor of Medicine, Stanford University, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.
Xigris® (drotrecogin alfa [activated]), a recombinant form of human activated protein C, received FDA approval in November 2001 for the reduction of mortality in adult patients with severe sepsis with a high risk of death. This approval was largely based on the PROWESS trial, in which Xigris administration was associated with a significant reduction in 28-day all-cause mortality relative to placebo administration.1 In practice, however, its use was often limited by its cost and a significant risk of serious bleeding episodes, as well questions about study design, the results achieved in some subsets of patients, and disputes about the amount of benefit associated with its use. These considerations, together with a European Union regulatory commitment, led Eli Lilly and Company to perform the PROWESS-SHOCK trial, another randomized, multinational, placebo-controlled, double-blind study to assess the effectiveness of drug in adults with septic shock.2
While the trial results are as yet unpublished, there was no apparent survival benefit associated with the use of Xigris. Results based on preliminary analyses done by Eli Lilly and Company and submitted to the FDA showed a 28-day all-cause mortality rate of 26.4% (223/846) in Xigris-treated patients compared to 24.2% (202/834) in placebo-treated patients, for a relative risk of 1.09 (95% confidence interval, 0.92-1.28; P = 0.31, not statistically significant).3
It is possible that both the earlier and the current results were correct for their times. Thus, the advances in management of sepsis and septic shock may have led to improved outcomes that could not be further advanced by Xigris. Nonetheless, as a consequence of this result, Eli Lilly and Company has voluntarily removed Xigris from the world-wide market.3
- Bernard GR, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344: 699-709.
- Silva E, et al. Prowess-shock trial: A protocol overview and perspectives. Shock 2010;34(Suppl 1):48-53.
- FDA. FDA drug safety communication: Voluntary market withdrawal of Xigris [dtrotrecogin alfa (activated)] due to failure to show a survival benefit. Available at: www.fda.gov/Drugs/DrugSafety/ucm277114.htm. Accessed Nov. 11, 2011.