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Activated protein C and septic shock: A propensity-matched cohort study*

Rimmer, Emily MD; Kumar, Anand MD; Doucette, Steve MSc; Marshall, John MD; Dial, Sandra MD; Gurka, David MD; Dellinger, R. Phillip MD, MCCM; Sharma, Satendra MD; Penner, Charles MD; Kramer, Andreas MD; Wood, Kenneth DO; Ronald, John MD; Kumar, Aseem PhD; Turgeon, Alexis F. MD; Houston, Donald S. MD, PhD; Zarychanski, Ryan MD; The Co-operative Antimicrobial Therapy of Septic Shock (CATSS) Database Research Group

Critical Care Medicine:
doi: 10.1097/CCM.0b013e31825fd6d9
Clinical Investigations
Abstract

Background: Septic shock is a highly inflammatory and procoagulant state associated with significant mortality. In a single randomized controlled trial, recombinant human activated protein C (drotrecogin alfa) reduced mortality in patients with severe sepsis at high risk of death. Further clinical trials, including a recently completed trial in patients with septic shock, failed to reproduce these results.

Objective: To evaluate the effectiveness of recombinant human activated protein C on mortality in a cohort of patients with septic shock and to explore possible reasons for inconsistent results in previous studies.

Design: Retrospective, 2:1 propensity-matched, multicenter cohort study.

Setting: Twenty-nine academic and community intensive care units in three countries.

Patients: Seven thousand three hundred ninety-two adult patients diagnosed with septic shock, of which 349 received recombinant human activated protein C within 48 hrs of intensive care unit admission between 1997 and 2007.

Measurements and Main Results: Our primary outcomes were mortality over 30 days and mortality stratified by Acute Physiology and Chronic Health Evaluation II quartile. Using a propensity-matched Cox proportional hazard model, we observed a 6.1% absolute reduction in 30-day mortality associated with the use of recombinant human activated protein C (108/311 [34.7%] vs. 254/622 [40.8%], hazard ratio 0.72, 95% confidence interval 0.52–1.00, p = .05) and noted consistent reductions in mortality among Acute Physiology and Chronic Health Evaluation II quartiles. A time to event analysis showed that the time to appropriate antimicrobials after documented hypotension decreased for each year of study (p = .003), a finding that was congruent with a decrease in annual mortality over the study period (odds ratio 0.96 per year [95% confidence interval 0.93–0.99], p = .003).

Conclusions: In this retrospective, propensity-matched, multicenter cohort study of patients with septic shock, early use of recombinant human activated protein C was associated with reduced mortality. Improvements in general quality of care such as speed of antimicrobial delivery leading to decreasing mortality of patients with septic shock may have contributed to the null results of the recently completed trial of recombinant human activated protein C in patients with septic shock.

Author Information

From the Department of Internal Medicine (ER, AnKu, DSH, RZ), University of Manitoba, Winnipeg, Canada; Department of Medical Oncology and Haematology (ER, DSH, RZ), CancerCare Manitoba, Winnipeg, Canada; Section of Critical Care Medicine (AnKu, SS), University of Manitoba, Winnipeg, Canada; Section of Critical Care Medicine (AnKu, PD), Cooper Hospital/University Medical Center, University of Medicine and Dentistry of New Jersey, Camden, NJ; Capital District Health Authority (StD), Halifax, Canada; Section of Critical Care Medicine (JM), St. Michael’s Hospital, Toronto, Canada; Section of Critical Care Medicine (SaD), Jewish General Hospital, Montreal, Canada; Section of Critical Care Medicine (DG), Rush Medical Center/Rush University, Chicago, IL; Section of Critical Care Medicine (CP, AnKr), Brandon Regional Health Authority, Brandon, Canada; Section of Pulmonary and Critical Care Medicine (KW), University of Wisconsin Hospital and Clinics, Madison, WI; Section of Critical Care Medicine (JR), Nanaimo Regional Hospital, Nanaimo, Canada; Laurentian University (AsKu), Sudbury, Canada; Centre de Recherche du Centre hospitalier affilié universitaire de Québec (Hôpital de l’Enfant-Jésus) (CHA-Research Center, Enfant-Jésus Hospital) (AFT), Traumatologie - Urgence - Soins Intensifs (Trauma - Emergency - Critical Care Medicine), Université Laval, Québec, QC, Canada; and Department of Community Health Sciences (RZ), University of Manitoba, Winnipeg, Canada.

*See also p. 3090.

Dr. Zarychanski is a recipient of a RCT mentoring award from the Canadian Institutes of Health Research (CIHR) and receives research support from CIHR, the Manitoba Health Research Council, and CancerCare Manitoba.

Dr. Marshall is a consultant for Eli Lilly, Eisai, and receives honoraria from Biomerica, Calgene, Data Safety Monitoring Board, Artisan Data Safety Monitoring Board. The remaining authors have not disclosed any potential conflicts of interest.

Address requests for reprints to: Ryan Zarychanski, MD, MSc, FRCPC, CancerCare Manitoba, ON2051-675 McDermot Ave, Winnipeg, Manitoba, Canada. E-mail: ryan.zarychanski@cancercare.mb.ca

© 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins