International integrated database for the evaluation of severe sepsis and drotrecogin alfa (activated) therapy: Analysis of efficacy and safety data in a large surgical cohort

• Published in: Surgery Vol. 141; no. 4; pp. 548 - 561
• Main Authors: Payen, Didier, MD, PhD, Sablotzki, Armin, MD, PhD, Barie, Philip S., MD, MBA, Ramsay, Graham, MD, PhD, Lowry, Stephen, MD, Williams, Mark, MD, Sarwat, Samiha, MS, Northrup, Justin, MPT, Toland, Patricia, RN, MS, MBA, McL. Booth, Frank V., MD
• Format: Journal Article
• Language: English
• Published: United States Mosby, Inc 01.04.2007
• Subjects: Aged; Anti-Infective Agents - adverse effects; Anti-Infective Agents - therapeutic use; Female; Hemorrhage - etiology; Humans; Male; Middle Aged; Protein C - adverse effects; Protein C - therapeutic use; Recombinant Proteins - adverse effects; Recombinant Proteins - therapeutic use; Retrospective Studies; Sepsis - drug therapy; Surgery; Treatment Outcome
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/j.surg.2007.02.004

Background The International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy includes an extensive cohort of surgical patients (1659/4459; 37%). This database broadens the experience reported on a comparatively small set of surgical patients from the pivotal Protein C Worldwide Evaluation in Severe Sepsis trial to examine issues of safety and efficacy in a much larger cohort. Methods We conducted a retrospective analysis of prospectively defined outcomes from 5 integrated clinical studies of severe sepsis. Multivariable analyses incorporated propensity scores, treatment, and significant baseline risk factors as independent variables in logistic regression models for 2 outcomes: serious adverse events that were observed during infusion and 28-day, all-cause mortality rates. Adjusted odds ratios were calculated for clinically important strata. Multiple subcategories of serious bleeding-event rates are presented. Results Although surgical patients who were treated with drotrecogin alfa [activated] (DrotAA) experienced a greater proportion of serious bleeding events during the infusion period, most of the patients were treated without fatal consequence. A 10.7% absolute all cause mortality risk reduction (adjusted odds ratio, 0.66; 95% CI, 0.45-0.97) was observed for DrotAA-treated, high-risk (Acute Physiology and Chronic Health Evaluation II, ≥25) surgical patients. We could not demonstrate a survival benefit in DrotAA-treated, low-risk (Acute Physiology and Chronic Health Evaluation II, <25) surgical patients. When surgical patients were stratified by number of organ dysfunctions, absolute risk reductions were observed in both categories: multiorgan (4.3%) and single (4.5%). Conclusion International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy analyses affirmed the favorable benefit/risk profile of DrotAA for surgical patients. The serious adverse event rate that was experienced by surgical patients during the study drug infusion period was 7.5% in the DrotAA-treated group versus 6.3% in the placebo-treated group (odds ratio, 1.41; 95% CI, 0.89-2.25). The clinical benefit of DrotAA therapy paralleled baseline risk of death and substantiated findings from the Protein C Worldwide Evaluation in Severe Sepsis study. Future analyses are needed to evaluate the special relationships among sepsis severity, bleeding management, and the postoperative timing of DrotAA administration.