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Stress ulcer prophylaxis with proton pump inhibitors or histamin-2 receptor antagonists in adult intensive care patients: a systematic review with meta-analysis and trial sequential analysis

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Abstract

Purpose

Most intensive care unit (ICU) patients receive stress ulcer prophylaxis. We present updated evidence on the effects of prophylactic proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RAs) versus placebo/no prophylaxis on patient-important outcomes in adult ICU patients.

Methods

We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomised clinical trials assessing the effects of PPI/H2RA versus placebo/no prophylaxis on mortality, gastrointestinal (GI) bleeding, serious adverse events (SAEs), health-related quality of life (HRQoL), myocardial ischemia, pneumonia, and Clostridium (Cl.) difficile enteritis in ICU patients.

Results

We identified 42 trials randomising 6899 ICU patients; 3 had overall low risk of bias. We did not find an effect of stress ulcer prophylaxis on mortality [relative risk 1.03, 95% confidence interval (CI) 0.94–1.14; TSA-adjusted CI 0.94–1.14], but the occurrence of any GI bleeding was reduced as compared with placebo/no prophylaxis (0.60, 95% CI 0.47–0.77; TSA-adjusted CI 0.36–1.00). The conventional meta-analysis indicated that clinically important GI bleeding was reduced (RR 0.63, 95% CI 0.48–0.81), but the TSA-adjusted CI 0.35–1.13 indicated lack of firm evidence. The effects of stress ulcer prophylaxis on SAEs, HRQoL, pneumonia, myocardial ischemia and Cl. difficile enteritis are uncertain.

Conclusions

In this updated systematic review, we were able to refute a relative change of 20% of mortality. The occurrence of GI bleeding was reduced, but we lack firm evidence for a reduction in clinically important GI bleeding. The effects on SAEs, HRQoL, pneumonia, myocardial ischemia and Cl. difficile enteritis remain inconclusive.

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Acknowledgements

MB, SM, JCJ, AP and JW were supported by the public Innovation Fund Denmark (4108-00011B), which did not have any role in study design, data collection, data analysis, data interpretation, or writing of the report. No other sources of financial support were obtained for this review. The authors thank Sanam Safi and Kiran Kumar Katakam, who were not involved in any aspects of the SUP-ICU trial, for extracting data and evaluating risk of bias of this trial. We also wish to thank Maria Hernandez Sierra, Aleksandra Mazur, Ning Liang and Dezhao Kong for translating papers.

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Authors and Affiliations

  1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, 2100, Copenhagen, Denmark

    Marija Barbateskovic, Janus Christian Jakobsen & Jørn Wetterslev

  2. Centre for Research in Intensive Care, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Marija Barbateskovic, Søren Marker, Janus Christian Jakobsen, Anders Perner, Jørn Wetterslev & Morten Hylander Møller

  3. Department of Intensive Care, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Søren Marker, Anders Granholm, Carl Thomas Anthon, Mette Krag, Anders Perner & Morten Hylander Møller

  4. Department of Cardiology, Holbaek Hospital, Holbaek, Denmark

    Janus Christian Jakobsen

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Correspondence to Marija Barbateskovic.

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Conflicts of interest

Marija Barbateskovic: PhD student at the Copenhagen Trial Unit and the Centre for Research in Intensive Care. Søren Marker: PhD student at the Department of Intensive Care at Rigshospitalet and the Centre for Research in Intensive Care. Coordinating investigator of the randomised clinical trial ‘Stress Ulcer Prophylaxis in the Intensive Care Unit’ (SUP-ICU). Anders Granholm: Coordinating investigator of the SUP-ICU trial. Carl Thomas Anthon: Coordinating investigator of the SUP-ICU trial. Mette Krag: Coordinating investigator of the SUP-ICU trial. Janus Christian Jakobsen: Director of Research, Chief Physician, Department of Cardiology, Holbæk Sygehus, Holbæk, Denmark. Anders Perner: Head of Research at the Department of Intensive Care at Rigshospitalet. The intensive care unit receives support for research from CSL Behring, Fresenius Kabi, Ferring Pharmaceuticals and the Novo Nordisk Foundation. Dr Perner is initiator of the SUP-ICU trial. Jørn Wetterslev: Member of the Copenhagen Trial Unit task force for developing Trial Sequential Analysis theory, manual and software which is presently free-ware at www.ctu.dk/tsa. Dr Wetterslev is member of the SUP-ICU trial steering group. Morten Hylander Møller: Sponsor and initiator of the SUP-ICU trial.

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Barbateskovic, M., Marker, S., Granholm, A. et al. Stress ulcer prophylaxis with proton pump inhibitors or histamin-2 receptor antagonists in adult intensive care patients: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 45, 143–158 (2019). https://doi.org/10.1007/s00134-019-05526-z

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