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Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical VentilationThe PEPTIC Randomized Clinical Trial

Educational Objective
To understand the benefits and risks of stress ulcer prophylaxis drugs for critically ill patients.
1 Credit CME
Key Points

Question  What is the comparative effect on in-hospital mortality of using proton pump inhibitors (PPIs) vs histamine-2 receptor blockers (H2RBs) for stress ulcer prophylaxis among adults requiring invasive mechanical ventilation in the intensive care unit (ICU)?

Findings  In this cluster crossover randomized clinical trial, 26 982 patients requiring invasive mechanical ventilation within 24 hours of ICU admission were randomized by site at 50 ICUs in 5 countries to a PPI strategy or an H2RB strategy for stress ulcer prophylaxis. In-hospital mortality was 18.3% for patients treated at sites randomized to PPI use vs 17.5% for those treated at sites randomized to H2RB use, a difference that did not reach statistical significance (P = .054). Among patients treated at sites randomized to PPIs, 4.1% received H2RBs; among patients treated at sites randomized to H2RBs, 20.1% received PPIs.

Meaning  A strategy of use with PPIs vs H2RBs for stress ulcer prophylaxis among adults requiring mechanical ventilation did not result in a statistically significant difference for in-hospital mortality, but study interpretation may be limited by crossover in medication use.

Abstract

Importance  Proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs) are often prescribed for patients as stress ulcer prophylaxis drugs in the intensive care unit (ICU). The comparative effect of these drugs on mortality is unknown.

Objective  To compare in-hospital mortality rates using PPIs vs H2RBs for stress ulcer prophylaxis.

Design, Setting, and Participants  Cluster crossover randomized clinical trial conducted at 50 ICUs in 5 countries between August 2016 and January 2019. Patients requiring invasive mechanical ventilation within 24 hours of ICU admission were followed up for 90 days at the hospital.

Interventions  Two stress ulcer prophylaxis strategies were compared (preferential use with PPIs vs preferential use with H2RBs). Each ICU used each strategy sequentially for 6 months in random order; 25 ICUs were randomized to the sequence with use of PPIs and then use of H2RBs and 25 ICUs were randomized to the sequence with use of H2RBs and then use of PPIs (13 436 patients randomized by site to PPIs and 13 392 randomized by site to H2RBs).

Main Outcomes and Measures  The primary outcome was all-cause mortality within 90 days during index hospitalization. Secondary outcomes were clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay.

Results  Among 26 982 patients who were randomized, 154 opted out, and 26 828 were analyzed (mean [SD] age, 58 [17.0] years; 9691 [36.1%] were women). There were 26 771 patients (99.2%) included in the mortality analysis; 2459 of 13 415 patients (18.3%) in the PPI group died at the hospital by day 90 and 2333 of 13 356 patients (17.5%) in the H2RB group died at the hospital by day 90 (risk ratio, 1.05 [95% CI, 1.00 to 1.10]; absolute risk difference, 0.93 percentage points [95% CI, −0.01 to 1.88] percentage points; P = .054). An estimated 4.1% of patients randomized by ICU site to PPIs actually received H2RBs and an estimated 20.1% of patients randomized by ICU site to H2RBs actually received PPIs. Clinically important upper gastrointestinal bleeding occurred in 1.3% of the PPI group and 1.8% of the H2RB group (risk ratio, 0.73 [95% CI, 0.57 to 0.92]; absolute risk difference, −0.51 percentage points [95% CI, −0.90 to −0.12 percentage points]; P = .009). Rates of Clostridioides difficile infection and ICU and hospital lengths of stay were not significantly different by treatment group. One adverse event (an allergic reaction) was reported in 1 patient in the PPI group.

Conclusions and Relevance  Among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of proton pump inhibitors vs histamine-2 receptor blockers resulted in hospital mortality rates of 18.3% vs 17.5%, respectively, a difference that did not reach the significance threshold. However, study interpretation may be limited by crossover in the use of the assigned medication.

Trial Registration  anzctr.org.au Identifier: ACTRN12616000481471

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Article Information

Accepted for Publication: December 19, 2019.

Corresponding Author: Paul J. Young, PhD, Intensive Care Unit, Wellington Hospital, Private Bag 7902, Wellington South, New Zealand (paul.young@ccdhb.org.nz).

Published Online: January 17, 2020. doi:10.1001/jama.2019.22190

Authors/Members of the PEPTIC Trial Writing Committee: Paul J. Young, PhD; Sean M. Bagshaw, MD; Andrew B. Forbes, PhD; Alistair D. Nichol, PhD; Stephen E. Wright, MBChB; Michael Bailey, PhD; Rinaldo Bellomo, PhD; Richard Beasley, DSc; Kathy Brickell, RN; Glenn M. Eastwood, PhD; David J. Gattas, MD; Frank van Haren, PhD; Edward Litton, PhD; Diane M. Mackle, MN; Colin J. McArthur, MBChB; Shay P. McGuinness, MD; Paul R. Mouncey, MSc; Leanlove Navarra, RN; Dawn Opgenorth, RN; David Pilcher, MBBS; Manoj K. Saxena, PhD; Steve A. Webb, PhD; Daisy Wiley, BSc; Kathryn M. Rowan, PhD.

Affiliations of Authors/Members of the PEPTIC Trial Writing Committee: Medical Research Institute of New Zealand, Wellington (Young, Beasley, Mackle, McArthur, McGuinness, Navarra); Intensive Care Unit, Wellington Hospital, Wellington, New Zealand (Young); Department of Critical Care Medicine, University of Alberta Hospital, Edmonton, Canada (Bagshaw, Opgenorth); Biostatistics Unit, Monash University, Melbourne, Australia (Forbes); Intensive Care Unit, Alfred Hospital, Melbourne, Australia (Nichol, Pilcher); Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia (Nichol, Bailey, Bellomo, Pilcher); University College Dublin-Clinical Research Centre, St Vincent’s Hospital, Dublin, Ireland (Nichol, Brickell); Intensive Care Unit, Freeman Hospital, Newcastle upon Tyne, England (Wright); University of Melbourne, Melbourne, Australia (Bailey, Bellomo); Intensive Care Unit, Austin Hospital, Heidelberg, Australia (Bellomo, Eastwood); Intensive Care Unit, Royal Prince Alfred Hospital, Camperdown, Australia (Gattas); George Institute for Global Health, University of New South Wales, Sydney, Australia (Gattas, Saxena); Intensive Care Unit, Canberra Hospital, Canberra, Australia (van Haren); Intensive Care Unit, Fiona Stanley Hospital, Murdoch, Australia (Litton); Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand (McArthur); Cardiothoracic and Vascular Intensive Care Unit, Auckland City Hospital, Auckland, New Zealand (McGuinness); Intensive Care National Audit and Research Centre, London, England (Mouncey, Wiley, Rowan); Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation, Camberwell, Australia (Pilcher); Intensive Care Unit, Bankstown Hospital, Bankstown, Australia (Saxena); Intensive Care Unit, Royal Perth Hospital, Perth, Australia (Webb).

Author Contributions: Drs Young and Forbes had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Young, Forbes, Bellomo, Eastwood, Gattas, van Haren, Litton, Mackle, McArthur, McGuinness, Pilcher, Saxena, Webb.

Acquisition, analysis, or interpretation of data: Young, Bagshaw, Forbes, Nichol, Wright, Bailey, Bellomo, Beasley, Brickell, Eastwood, Gattas, van Haren, Litton, Mackle, McArthur, McGuinness, Mouncey, Navarra, Opgenorth, Pilcher, Webb, Wiley, Rowan.

Drafting of the manuscript: Young, Forbes, Nichol, Wright, Bellomo, Pilcher.

Critical revision of the manuscript for important intellectual content: Young, Bagshaw, Forbes, Nichol, Wright, Bailey, Bellomo, Beasley, Brickell, Eastwood, Gattas, van Haren, Litton, Mackle, McArthur, McGuinness, Mouncey, Navarra, Opgenorth, Pilcher, Saxena, Webb, Wiley, Rowan.

Statistical analysis: Young, Forbes, Bailey.

Obtained funding: Young, Bagshaw, Nichol, McGuinness, Pilcher.

Administrative, technical, or material support: Bagshaw, Beasley, Eastwood, Mackle, McGuinness, Mouncey, Navarra, Opgenorth, Pilcher, Wiley, Rowan.

Supervision: Young, Nichol, Wright, Bellomo, McGuinness, Pilcher, Saxena, Rowan.

Conflict of Interest Disclosures: Dr Bagshaw reported receiving grants and personal fees from Baxter; and personal fees from Spectral Medical and CNA Diagnostics. Dr Beasley reported receiving grants and personal fees from AstraZeneca and GlaxoSmithKline. No other disclosures were reported.

Funding/Support: Funded by the Health Research Council of New Zealand, the Canadian Institutes of Health Research, the Australian and New Zealand Intensive Care Foundation, and the Health Research Board of Ireland. The PEPTIC trial was supported by the UK National Institute for Health Research Critical Care Clinical Research Networks and the UK Critical Care Research Group.

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

The PEPTIC Trial Members: The members of the writing committee are Paul J. Young, PhD (Medical Research Institute of New Zealand, Wellington; and Wellington Hospital, Wellington, New Zealand), Sean M. Bagshaw, MD (University of Alberta Hospital, Edmonton, Alberta, Canada), Alistair D. Nichol, PhD (Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia; the Alfred Hospital, Melbourne, Australia; and St Vincent’s Hospital, Dublin, Ireland), Stephen E. Wright, MBChB (Dorset County Hospital, Dorchester, England), Rinaldo Bellomo, PhD (Austin Hospital, Heidelberg, Australia; Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia; and the University of Melbourne, Melbourne, Australia), Richard Beasley, DSc (Medical Research Institute of New Zealand, Wellington), Kathy Brickell, RN (St Vincent’s Hospital, Dublin, Ireland), Glenn M. Eastwood, PhD (Austin Hospital, Heidelberg, Australia), David J. Gattas, MD (Royal Prince Alfred Hospital, Sydney, Australia), Frank van Haren, PhD (Canberra Hospital, Canberra, Australia), Edward Litton, PhD (Fiona Stanley Hospital, Perth, Australia), Diane Mackle, MN (Medical Research Institute of New Zealand, Wellington), Colin J. McArthur, MBChB (Medical Research Institute of New Zealand, Wellington; and Auckland City Hospital, Auckland, New Zealand), Shay P. McGuinness, MD (Medical Research Institute of New Zealand, Wellington; and Auckland City Hospital, Auckland, New Zealand), Paul R. Mouncey, MSc (Intensive Care Audit and Research Centre, London, England), Leanlove Navarra, RN (Medical Research Institute of New Zealand, Wellington), Dawn Opgenorth, RN (University of Alberta Hospital, Edmonton, Canada), David Pilcher, MD (Alfred Hospital, Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation; and Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia), Manoj K. Saxena, PhD (Intensive Care Unit, Bankstown Hospital; and the George Institute for Global Health, University of New South Wales, Sydney, Australia), Steve A. Webb, PhD (Royal Perth Hospital, Perth, Australia), Daisy Wiley, BSc (Intensive Care Audit and Research Centre, London, England), and Kathryn M. Rowan, PhD (Intensive Care Audit and Research Centre, London, England). Site Investigators and Research Coordinators:Australia: Alfred Hospital: Jasmin Board, MPH, Melanie Kowalski, Phoebe McCracken, MPH, David Pilcher, MBBS, FCICM, Shirley Vallance, and Meredith Young, MPH; Austin Hospital: Rinaldo Bellomo, PhD, Glenn Eastwood, PhD, Leah Peck, and Helen Young; Bendigo Hospital: Catherine Boschert, PGCert, Jason Fletcher, MBBS, and Julie Smith, PGDip; Canberra Hospital: Katie Jefferson, Elyse Ladbrook, Mary Nourse, PGCert, Shakira Spiller, MCCM, and Frank Van Haren, PhD; Concord Hospital: Rosalba Cross, MBBS, and Helen Wong, RN; Fiona Stanley Hospital: Mason Johnstone, Edward Litton, PhD, Annemaria Palermo, BA, and Susan Pellicano; Footscray Hospital: Samantha Bates, GradDip Crit Care, Craig French, FCICM, Anna Tippett, GradDip Sci, and Miriam Towns, MPH; Gold Coast University Hospital: Maimoonbe Gough, RN, David Pearson, FCICM, Mandy Tallott, MCCN, and Rosemary Willis, RN; Launceston Hospital: Matthew Brain, MBBS, and Sarah Mineall, MCN; Nepean Hospital: Rebecca Gresham, RN, Julie Lowrey, BH, Kristy Masters, RN, Ian Seppelt, MBBS, and Christina Whitehead, MBioethics; Northern Hospital: Angaj Ghosh, FCICM, and Simone Said, PGDip; Rockingham Hospital: Kartik Atre, MClinEpid, and Ravi Sonawane, MPH; Royal Hobart Hospital: David Cooper, FCICM, and Rick McAllister; Royal Melbourne Hospital: Deborah Barge, CCRN, Kathleen Byrne, MNS, Andrea Jordan, RN, Christopher MacIsaac, PhD, Jeffrey Presneill, PhD, Thomas Rechnitzer, MBBS, and Shyamala Sriram, MBBS; Royal Perth Hospital: Sharon Waterson, PGDip, and Steve Webb, PhD; Royal Prince Alfred Hospital: Heidi Buhr, MScMed, Jennifer Coles, Dip Adult Nursing, David Gattas, MD, Debra Hutch, MIntensive Care, and James Wun, GradCert Crit Care; St George Hospital: Deborah Inskip, PGCert, Jennene Miller, PGCert, and Manoj Saxena, PhD; St Vincent’s Hospital (Melbourne): Jenny Holmes, PGDip AdvN, Daniel Lim, MPharmPrac, John Santamaria, MD BS, and Roger Smith, MPH; St Vincent’s Hospital (Sydney): Nerilee Baker, Hergen Buscher, Karlee McCann, MHSc, Priya Nair, PhD, and Claire Reynolds; Sunshine Hospital (Western Health): Samantha Bates, GradDip Crit Care, Craig French, FCICM, Anna Tippett, GradDip Sci, and Miriam Towns, MPH; Wollongong Hospital: Wenli Geng, MSN, Samantha Jakimowicz, RN, and Martin Sterba, PhD. Canada:Grey Nuns Community Hospital: Dominic Carney, MD, Krista Dewart, MN, Larissa Fedor, BSc, and Melissa Ziober, BScN; Mazankowski Alberta Heart Institute: David Diachinsky, BScN, Sean Van Diepen, MD, Mohamed Omar, PharmaD, Desiree Ross, BScN, and Ruth Santos, BScN; Misericordia Community Hospital: Erika McIntyre, MD, Patricia O’Toole, RN, Ella Rokosh, MD, and Robin Scheelar, BScPharm; Red Deer Regional Hospital: Gillian Brown, BScN, Kerry Oxtoby, BScN, Carmen Petersen, RN, and Michael Russell, MD; Royal Alexandra Hospital: Jon Davidow, MD, Ken Forgach, BScPharm, and Tove LaBlanc, BScN; Sturgeon Community Hospital: Castro Aris, MN, Shirley Baumgartner, RN, Glenda Corrigal, RN, Nancy Coyne, BScN, Kristina Dover, BScPharm, Celine Pelletier, NP, Oleksa Rewa, MD, Kim Spears, BScPharm, and Gabriel Suen, MD; University of Alberta Hospital: Sean Bagshaw, MD, Catherine Sych, PharmaD, Samantha Taylor, MPH, and Derek R. Townsend, MD; University of Alberta Hospital (Neurosciences): Peter Brindley, MD, Dyan Franco, RN, Paul Gerun, BScN, Crystal Hancheruk, BScN, Jim Kutsogiannis, MD, Pam Lavallee, RN, and Spencer Ling, PharmaD. England:Basingstoke and North Hampshire Hospital: Clarisse Carreiras, MRes, Richard Partridge, MBBS, Nycola Muchenje, BSc, McDonald Mupudzi, BSc, and Denise Griffin, RGN; County Durham and Darlington NHS Foundation Trust: Amanda Cowton, BSc, Chris Dawson, MBChB, Louise Duncan, BSc, and James Limb, BMBS; Dorset County Hospital: Mark Pulletz, MBBS, and Patricia Williams, Adv Dip; Freeman Hospital: Maite Babio-Galan, PGCert, and Stephen Wright, MBChB; James Cook University Hospital: Jeremy Henning, MBBCh, and Keith Hugill, BSc; North Cumbria University Hospitals NHS Trust: Tim Smith, MBBCh, and Toni Wilson, RGN; Northern Specialist Emergency Care Hospital: Bryan Yates, MBBS; Poole Hospital: Julie Camsooksai, BSc, and Henrik Reschreiter, FRCA, Dr Med; Queen Alexandra Hospital, Portsmouth: David Pogson, MSc, and Steve Rose, BSc; Queen Elizabeth Hospital, Gateshead: Vanessa Linnett, MBBS, Amanda Sanderson, DipHE, and Jenny Ritzema, MSc; Royal Hampshire County Hospital: Nicole Gregerson, BSc, and Steve Wimbush, MBChB; Royal Victoria Infirmary: Ian Clement, PhD, and Leigh Dunn, PGCert; Russells Hall Hospital: Clare Allcock, BA, and Julian Sonsken, MBChB; University Hospital of North Tees: Michele Clark, BSc, and Hemal Mohan MBBS. Ireland:St Vincent’s Hospital (Dublin): Kathy Brickell, RN, Leanne Hays, PhD, Nicola Hyde, RN, Alistair Nichol, PhD, Mary O’Sullivan, MSc Pharmacy, and Michelle Smyth, PGDip. New Zealand:Auckland City Hospital (Cardiothoracic and Vascular Intensive Care Unit): Aimee Blakemore, RN, Lejla Brkic, Magdalena Butler, PGCert, Keri-Anne Cowdrey, PGCert, Eileen Gilder, MHealth Promotion and Health Ed, Jane Hallion, PGCert, Stephnie Long, PGDip, Shay McGuinness, MD, Rachael Parke, PhD, and Samantha Ryan, PGDip; Middlemore Hospital: Jefferson Aguila, PGCert Health Sci, Bernadette Clatworthy, PGDip Health Sci, Anisha Dias, PGDip Health Sci, Alex Kazemi, FCICM, Vivian Lai, MHC, and Rima Song, PGDip Health Sci; Nelson Hospital: Alex Browne, MBChB, Petra Crone, PGDip, Annette Egan, MClin Pharm, Kylie Fenwick, PGCert, and Charlotte McNab, PGCert; North Shore Hospital: Maud Carpenter, PGDip, Rica Dagooc, PGDip, Danni Hacking, PGDip, Jessica Nand, PGDip, and Ywain Lawrey, FCICM; Tauranga Hospital: Troy Browne, MBChB, Jennifer Goodson, DCN, and Shirley Nelson, RN; Waikato Hospital: Jewel Barlow-Armstrong, MEd, Annette Forrest, FCICM, Caitriona Fiske, PGCert Health Sci, Sarah Rogers, and Kara Trask, PGCert; Wellington Hospital: Ben Barry, FCICM, Dick Dinsdale, FCICM, Caitlin Firkin, MBusAn, Frances Fitzjohn, Peter Hicks, FCICM, Georgia Hill, MClinIm, Anna Hunt, RN, Harriet Judd, PGDip Health Care, Cassie Lawrence, RN, Eden Lesona, MNS, Agnes McKay-Vucago, MPPNursing, Nicholas On, MBChB, Christopher Poynter, FCICM, Alex Psirides, FCICM, Raulle Sol Cruz, BSN, Shawn Sturland, FCICM, Kate Tietjens, FCICM, Robert Ure, FCICM, and Paul Young, PhD.

Meeting Presentation: Presented in part at the Critical Care Reviews meeting; January 17, 2020; Belfast, Northern Ireland.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the members of the data and safety monitoring committee: Brian Cuthbertson, MD (chair), Anthony Gordon, MD, and Graeme MacLennan, MSc. We thank the study statisticians: Andrew B. Forbes, PhD (Monash University, Melbourne, Australia), and Michael Bailey, PhD (Australian and New Zealand Intensive Care Research Centre, Monash University, and the University of Melbourne, Melbourne, Australia). We thank the members of the study coordinating centers: Malik Agyemang, PhD, Sean Bagshaw, MD, Jo Harris, BSc, Dawn Opgenorth, RN, Stephanie Smith, MD, Xiaoming Wang, PhD, and Dan Zuege, MD (Alberta Health Services, Edmonton, Canada), Rinaldo Bellomo, PhD, Glenn Eastwood, PhD (Austin Hospital, Heidelberg, Australia), Kathy Brickell, RN, Peter Doran, PhD, Ciara Fahey, PhD, Patrick Murray, MD, and Alistair Nichol, PhD (Health Research Board Irish Critical Care Clinical Trials Network, University College Dublin-Clinical Research Centre at St Vincent’s University Hospital, Dublin, Ireland), Paul Mouncey, MSc, Kathy Rowan, PhD, and Daisy Wiley, BSc (Intensive Care National Audit and Research Centre, London, England), Tanya Baker, BA, BSc, Mark Holliday, BSc, Diane Mackle, MN, Carla McInnes, RN, Leanlove Navarra, RN, Nick Shortt, MClinRes, and Paul Young, PhD (Medical Research Institute of New Zealand, Wellington), and Stephen Wright, MBChB (Newcastle upon Tyne Hospitals NHS Foundation Trust, England).

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