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Activated protein C and hospital mortality in septic shock: A propensity-matched analysis*

Lindenauer, Peter K. MD, MSc; Rothberg, Michael B. MD, MPH; Nathanson, Brian H. PhD; Pekow, Penelope S. PhD; Steingrub, Jay S. MD

doi: 10.1097/CCM.0b013e3181d423b7
Clinical Investigations

Objective: Evidence regarding the efficacy and safety of human recombinant activated protein C in severe sepsis is limited, especially outside of clinical trials. We sought to compare the outcomes of patients with septic shock who received early treatment with activated protein C to those who did not.

Design, Setting, and Patients: A retrospective cohort study at 404 U.S. hospitals. We studied 33,749 patients with sepsis who were admitted to intensive care and administered antibiotics and vasopressors within 2 days of admission.

Measurements and Main Results: Hospital mortality, intracranial and gastrointestinal hemorrhage, major transfusion. Compared to the entire cohort, the 1576 activated protein C-treated patients included in the matched analysis were younger (mean age, 61 vs. 67), more likely to be white (70% vs. 63%), and had fewer comorbidities. Treated patients were more likely to require mechanical ventilation (77% vs. 48%), to be administered two or more vasopressors (68% vs. 41%), to undergo pulmonary artery catheterization (9% vs. 4%), and to die in the hospital (40.7% vs. 38.1%). In a propensity-matched sample in which all covariates achieved balance, receipt of activated protein C was associated with reduced hospital mortality (40.7% vs. 46.6%; risk ratio, 0.87; 95% confidence interval, 0.80-0.95). This result was insensitive to a hypothetical unmeasured confounder. A similar pattern was observed across groups stratified by age and number of organ-supportive therapies. Four activated protein C-treated patients (0.25%) had hemorrhagic stroke, 107 (6.8%) had gastrointestinal bleeding, and five (0.3%) required major transfusion.

Conclusions: Among patients presenting with septic shock, early treatment with activated protein C may be associated with reduced hospital mortality.

From Center for Quality of Care Research (PKL, MBR, PSP), Division of General Internal Medicine and Geriatrics (MBR), and Division of Critical Care (JSS), Baystate Medical Center, Springfield, MA; Department of Medicine (PKL, MBR, JSS), Tufts University School of Medicine, Boston, MA; OptiStatim LLC (BHN), Longmeadow, MA; School of Public Health and Health Sciences (PSP), University of Massachusetts-Amherst, Amherst, MA.

Financial support was received from Division of Critical Care Medicine, Baystate Medical Center, Springfield, MA. Premier Healthcare Informatics, Charlotte, NC, provided the data used to conduct this study but had no role in its design, conduct, analysis, interpretation of data, or the preparation, review, or approval of the manuscript.

Drs. Lindenauer, Rothberg, Nathanson, and Pekow have not disclosed any potential conflicts of interest. Dr. Rothberg is the recipient of a clinical scientist development award from the Doris Duke Charitable Foundation. Dr. Steingrub participates on the speaker's bureau of Eli Lilly & Company. Dr. Nathanson, through his company OptiStatim LLC, was paid by the investigators with funding from the Division of Critical Care Medicine at Baystate Medical Center to assist in conducting the statistical analyses in this study.

Dr. Lindenauer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Lindenauer, Steingrub, and Rothberg conceived the study. Dr. Lindenauer acquired the data. Drs. Lindenauer, Rothberg, Steingrub, Nathanson, and Pekow analyzed and interpreted the data. Dr. Lindenauer drafted the manuscript. Drs. Rothberg, Nathanson, Pekow, and Steingrub critically reviewed the manuscript for important intellectual content. Drs. Nathanson and Pekow performed the statistical analyses. Dr. Pekow accepts full responsibility for its accuracy.

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© 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins