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Withholding Pantoprazole for Stress Ulcer Prophylaxis in Critically Ill Patients: A Pilot Randomized Clinical Trial and Meta-Analysis*

Alhazzani, Waleed MD1,2; Guyatt, Gordon MD1,2; Alshahrani, Mohammed MD3; Deane, Adam M. MBBS4; Marshall, John C. MD5; Hall, Richard MD6; Muscedere, John MD7; English, Shane W. MD8,9; Lauzier, François MD10; Thabane, Lehana PhD2,11; Arabi, Yaseen M. MD12; Karachi, Tim MD1; Rochwerg, Bram MD1,2; Finfer, Simon MBBS13; Daneman, Nick MD14; Alshamsi, Fayez MD15; Zytaruk, Nicole RN2; Heel-Ansdell, Diane MSc2; Cook, Deborah MD1,2; on behalf of the Canadian Critical Care Trials Group

doi: 10.1097/CCM.0000000000002461
Feature Articles

Introduction: A decreased frequency of upper gastrointestinal bleeding and a possible association of proton pump inhibitor use with Clostridium difficile and ventilator-associated pneumonia have raised concerns recently. The Reevaluating the Inhibition of Stress Erosions Pilot Trial determined the feasibility of undertaking a larger trial investigating the efficacy and safety of withholding proton pump inhibitors in critically ill patients.

Methods: In 10 ICUs, we randomized adult ICU patients anticipated to be mechanically ventilated for greater than or equal to 48 hours to receive 40 mg of IV pantoprazole daily or placebo. We excluded patients who had acute or recent gastrointestinal bleed, used dual antiplatelet agents, had a medical condition requiring proton pump inhibitor treatment, or had already received more than one dose of acid suppression daily. Patients, families, clinicians, and research staff were blinded. We conducted a systematic review and meta-analysis of similar trials.

Main Results: Ninety-one patients (49 pantoprazole and 42 placebo) from 10 centers in Canada, Saudi Arabia, and Australia were enrolled. All feasibility goals were met: 1) recruitment rate was 2.6 patients per month; 2) consent rate was 77.8%; and 3) protocol adherence was 97.7%. Upper gastrointestinal bleeding developed in 6.1% of patients in the pantoprazole group and 4.8% in the placebo group (p = 1.0). Ventilator-associated pneumonia developed in 20.4% of patients in the pantoprazole group and 14.3% in the placebo group (p = 0.58). C. difficile was identified in 4.1% pantoprazole patients and in 2.4% placebo patients (p = 1.0). We meta-analyzed five trials (604 patients) of proton pump inhibitors versus placebo; there was no statistically significant difference in the risk of upper gastrointestinal bleeding, infections, or mortality.

Conclusions: Our results support the feasibility of a larger trial to evaluate the safety of withholding stress ulcer prophylaxis. Although the results are imprecise, there was no alarming increase in the risk of upper gastrointestinal bleeding; the effect of proton pump inhibitors on ventilator-associated pneumonia and C. difficile remain unclear.

1Department of Medicine, McMaster University, Hamilton, ON, Canada.

2Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada.

3Department of Critical Care, University of Dammam, Dammam, Saudi Arabia.

4Discipline of Acute Care Medicine, University of Adelaide, Adelaide, SA, Australia.

5Department of Surgery and Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada.

6Departments of Anesthesia, Pain Management and Perioperative Medicine and Critical Care Medicine, Dalhousie University, Halifax, NS, Canada.

7Department of Critical Care, Queens University, Kingston, ON, Canada.

8Department of Medicine (Critical Care), University of Ottawa, Ottawa, ON, Canada.

9Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.

10Departments of Medicine, Anesthesiology and Critical Care, Université Laval, Quebec City, QC, Canada.

11Biostatistics Unit, St Joseph’s Healthcare Hamilton, Hamilton, ON, Canada.

12Intensive Care Department, King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.

13The George Institute for Global Health and Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.

14Department of Medicine, University of Toronto, Toronto, ON, Canada.

15Department of Internal Medicine, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.

*See also p. 1241.

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REVISE Pilot Trial was supported, in part, by Research Grants awarded by Physicians Services Incorporated of Ontario, Dammam University Research Funds, Capital Health Authority Research in Halifax, and the Royal Adelaide Hospital Project Committee.

Dr. Alhazzani holds a McMaster University Department of Medicine Internal Career Research Award. Dr. Guyatt’s institution received funding from Physicians Services Incorporated. Dr. Alshahrani’s institution received funding from University of Dammam deanship of research. Dr. Deane’s institution received funding from the Royal Adelaide Hospital Research Fund. Dr. Marshall received funding from Regeneron, AKPA Pharma, and Bristol-Myers Squibb. Dr. Hall’s institution received funding from La Jolla, E-Motion, Sunnybrook Medical Centre (Canadian Institutes of Health Research [CIHR] grant), McMaster University (CIHR grant), Queens University (CIHR grant), and he disclosed funding from Trius Therapeutics, Asahi Kasei Pharma, Leading Biosciences, Capital Health Research Fund, GlaxoSmithKline, Portola, and Pfizer. Dr. English’s institution received funding from the sponsoring centre and from La Jolla Pharmaceuticals for the Athos 3 trial. Dr. Lauzier is a recipient of a research career award from the Fonds de la recherche du Québec-Santé. Dr. Finfer’s institution received funding from Baxter Healthcare and Regeneron. Ms. Heel-Ansdell’s institution received funding from PSI Foundation Grant. Dr. Cook’s institution received funding from Physicians Services Incorporated of Ontario. She is a Canada Research Chair of the Canadian Institutes for Health Research. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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