© 2008 American Thoracic Society
Drotrecogin Alfa (Activated): Surviving Sepsis by ChanceTo the Editor:I read with interest the article on DrotAA by Levi and colleagues (1). Interestingly, trials with DrotAA have resulted in many publications based on ad hoc, post hoc, and subgroup analysis, raising the possibility of an unresolved quest for defining the role for this drug in critically ill patients. The approval by the Food and Drug Administration (FDA) in November, 2001, was based on a single phase III, randomized controlled trial (2). There were concerns that the approval of this drug for clinical use might be premature, and trials that followed subsequently were mandated by the FDA. Unfortunately, the enthusiasm for and widespread use of this drug were not matched by available evidence. However, noticeably, as in most of the trials using DrotAA, the frequency of authors who are employees and/or holders of stock and shares in the company that manufactures it are steadily increasing. In the study by Levi and colleagues (1), contrary to their stated inclusion criteria and objective, the trial included patients with an Acute Physiology Age and Chronic Health Evaluation (APACHE) II score < 25 (53% in the DrotAA + heparin and 55% in the DrotAA + placebo) and patients with two or less organ failures (28%). The lack of benefit of using DrotAA in this group of patients had already been demonstrated by the ADDRESS study (3). The authors state that since all patients received DrotAA, no conclusion can be made regarding the efficacy of DrotAA. However, the recent ADDRESS long-term follow-up study on safety and efficacy of DrotAA showed important results that should concern clinicians and the FDA (4). The 28-day mortality benefit noted in the PROWESS study, among the subgroup of patients with a high risk of dying defined by multiorgan failure or APACHE II > 25, was unfortunately not seen in a similar group of patients in the ADDRESS study and in the recently published ADDRESS long-term follow-up study (3, 4). The role of DrotAA in sepsis, including patients at high risk of dying, is questioned as trials show no benefit data to the clinician (5). Perhaps this drug may have a role in reducing ischemic strokes, as the authors pointed out. Clearly, there is an imminent need to clarify the role of DrotAA in severe sepsis. Until then more and more trials using DrotAA, such as PROWESS, ADDRESS, ADDRESS-2, and XPRESS, will reach the press.
The University of Texas M.D. Anderson Cancer Center FOOTNOTES Conflict of Interest Statement: The author has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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