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Quantifying the Effects of Prior Acetyl-Salicylic Acid on Sepsis-Related Deaths: An Individual Patient Data Meta-Analysis Using Propensity Matching*

Trauer, James MBBS, PhD1; Muhi, Stephen MBBS, MPHTM2; McBryde, Emma S. MBBS, PhD2,3; Al Harbi, Shmeylan A. PharmD4; Arabi, Yaseen M. MD5; Boyle, Andrew J. MD6; Cartin-Ceba, Rodrigo MD7,8; Chen, Wei MD9; Chen, Yung-Tai MD10; Falcone, Marco MD11; Gajic, Ognjen MD8; Godsell, Jack MBBS2; Gong, Michelle Ng MD12–14; Kor, Daryl MD15; Lösche, Wolfgang MD16; McAuley, Daniel F. MD17; O’Neal, Hollis R. Jr MD, MSc18; Osthoff, Michael MD19; Otto, Gordon P. MD, MSc20; Sossdorf, Maik PhD20; Tsai, Min-Juei MD21; Valerio-Rojas, Juan C. MD7,22; van der Poll, Tom MD, PhD23,24; Violi, Francesco MD25; Ware, Lorraine MD26; Widmer, Andreas F. MD, MS19; Wiewel, Maryse A. MD23,27; Winning, Johannes MD20; Eisen, Damon P. MBBS, MD2,28,29

doi: 10.1097/CCM.0000000000002654
Clinical Investigations

Objective: The primary objective was to conduct a meta-analysis on published observational cohort data describing the association between acetyl-salicylic acid (aspirin) use prior to the onset of sepsis and mortality in hospitalized patients.

Study Selection: Studies that reported mortality in patients on aspirin with sepsis with a comparison group of patients with sepsis not on prior aspirin therapy were included.

Data Sources: Fifteen studies described hospital-based cohorts (n = 17,065), whereas one was a large insurance-based database (n = 683,421). Individual-level patient data were incorporated from all selected studies.

Data Extraction: Propensity analyses with 1:1 propensity score matching at the study level were performed, using the most consistently available covariates judged to be associated with aspirin. Meta-analyses were performed to estimate the pooled average treatment effect of aspirin on sepsis-related mortality.

Data Synthesis: Use of aspirin was associated with a 7% (95% CI, 2–12%; p = 0.005) reduction in the risk of death as shown by meta-analysis with considerable statistical heterogeneity (I 2 = 61.6%).

Conclusions: These results are consistent with effects ranging from a 2% to 12% reduction in mortality risk in patients taking aspirin prior to sepsis onset. This association anticipates results of definitive studies of the use of low-dose aspirin as a strategy for reduction of deaths in patients with sepsis.

Supplemental Digital Content is available in the text.

1School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

2Victorian Infectious Diseases Service, The Doherty Institute, Melbourne, Victoria, Australia.

3Australian Institute of Tropical Medicine and Hygiene, James Cook University, Douglas, Queensland, Australia.

4Pharmaceutical Care Department, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia.

5Intensive Care Department, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.

6Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, Northern Ireland.

7Multidisciplinary Epidemiology and Translational Research in Intensive Care, Mayo Clinic, Rochester, MN.

8Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.

9Division of Pulmonary and Critical Medicine, Chiayi Christian Hospital, Chiayi, Taiwan.

10Department of Nephrology, Taipei City Hospital Heping Fuyou Branch, Taipei, Taiwan, Republic of China.

11Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, Rome, Italy.

12Division of Critical Care Medicine, Department of Medicine, Montefiore Medical Center, Bronx, NY.

13Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.

14Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY.

15Department of Anesthesiology, Division of Critical Care Medicine, Mayo Clinic, Rochester, MN.

16Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.

17Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, Northern Ireland.

18Louisiana State University Health Sciences Center, Department of Medicine, Section of Pulmonary and Critical Care Medicine, Baton Rouge, LA.

19Division of Infectious Diseases and Hospital Epidemiology, Department of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.

20Clinic for Anaesthesiology and Intensive Care Medicine, University Hospital Jena, Jena, Germany.

21Department of Internal Medicine, Taipei Veterans General Hospital, Taiwan, Republic of China.

22Department of Internal Medicine, Division of Critical Care Medicine, San Rafael Hospital, Alajuela, Costa Rica.

23Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

24Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

25Department of Internal Medicine and Medical Specialties, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy.

26Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN.

27The Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

28College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.

29Infectious Diseases Unit, The Townsville Hospital, Douglas, Queensland, Australia.

*See also p. 1959.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Drs. Gong, Kor, O’Neal, and Ware received support for article research from the National Institutes of Health (NIH). Dr. Gong’s institution received funding from the National Heart, Lung, and Blood Institute. Dr. Kor’s institution received funding from the NIH, and he disclosed off-label product use of aspirin. Dr. McAuley received funding from Peptinnovate, Bayer, GlaxoSmithKline, Boehringer Ingelheim (consulting). Outside the submitted work, his institution has received funds from grants from the U.K. National Institute for Health Research and others, and he is one of the four named inventors on a patent US8962032 covering the use of sialic acid–bearing nanoparticles as anti-inflammatory agents issued to his institution, The Queen’s University of Belfast ( Dr. Osthoff’s institution received funding from Pharming Technologies B.V. Dr. Ware’s institution received funding from the NIH, Boehringer Ingelheim, and Global Blood Therapeutics. Dr. Winning disclosed off-label product use of aspirin. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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