© 2008 American Thoracic Society
Drotrecogin Alfa (Activated): Surviving Sepsis by ChanceFrom the Authors:Commenting on our article (1), Dr. Pravinkumar expresses the opinion that multiple subgroup analyses from trials of recombinant human activated protein C (rhAPC) have been performed in a "quest" to better define the role of this agent in patients with severe sepsis. In fact, a large number of additional analyses of relevant clinical data from patients with severe sepsis who were treated with rhAPC or placebo have been published in peer-reviewed scientific journals. Obviously, the phase III PROWESS study was pivotal in the approval of rhAPC by the FDA and other regulatory agencies. However, other clinical data, for example, from the phase II clinical trial in patients with severe sepsis, as well as preclinical data, were important as well (2). We do not understand the remark on the number of authors who are employees or stockholders of the manufacturer of rhAPC in the various publications, including the XPRESS study, as this potential conflict of interest has always been reported up-front, and all authors are medical experts who meet the requirements for authorship. Despite the large burden of sepsis on society throughout the world, trials in patients with severe sepsis of this size would (unfortunately) hardly ever have been performed without important academic and industry partnerships. Unfortunately, Dr. Pravinkumar does not correctly cite the inclusion criteria of the XPRESS study. As clearly stated in the METHODS section of our article (1), an APACHE score of > 25 was not a strict inclusion criterion of this trial, as this is only part of the U.S. label, and in many other parts of the world the indication is based on the number of organ failures. Importantly, the XPRESS trial was designed at the same time of ADDRESS, and thus the results of ADDRESS had no impact on study design for XPRESS. We feel it is scientifically incorrect to use a subgroup analysis of patients with a relatively severe disease intensity from the ADDRESS trial, which primarily focused on patients with sepsis and a relatively low disease severity, to conclude that rhAPC is not effective in patients with an APACHE score of > 25. Nevertheless, we agree with Dr. Pravinkumar that, despite the solid data from PROWESS and other clinical studies with rhAPC, the role of this agent in the treatment of sepsis needs to be confirmed. Therefore, we are happy to report that a new randomized placebo-controlled trial of rhAPC in patients with septic shock is currently planned and will start enrollment in 2008.
University of Amsterdam
Rhode Island Hospital
Lilly Research Laboratories FOOTNOTES Conflict of Interest Statement: M. Levi has participated in previous trials sponsored by Eli Lilly and has served as paid consultant for Eli Lilly. M. Levy has received lecture fees from Eli Lilly and Edwards Lifesciences, as well as grants from Eli Lilly, Edwards Lifesciences, Philips Medical Systems, Novartis, and Biosite. M.D.W. is an employee of Eli Lilly. REFERENCES
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