Article Text

Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans
  1. Yan Xie1,
  2. Benjamin Bowe1,
  3. Tingting Li1,2,
  4. Hong Xian1,3,
  5. Yan Yan1,4,
  6. Ziyad Al-Aly1,2,5,6
  1. 1 Clinical Epidemiology Center, Research and Education Service, VA Saint Louis Health Care System, Saint Louis, Missouri, USA
  2. 2 Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA
  3. 3 Department of Biostatistics, College for Public Health and Social Justice, Saint Louis University, Saint Louis, Missouri, USA
  4. 4 Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA
  5. 5 Renal Section, Medicine Service, VA Saint Louis Health Care System, Saint Louis, Missouri, USA
  6. 6 Institute for Public Health, Washington University in Saint Louis, Saint Louis, Missouri, USA
  1. Correspondence to Dr Ziyad Al-Aly; zalaly{at}gmail.com

Abstract

Objective Proton pump inhibitors (PPIs) are widely used, and their use is associated with increased risk of adverse events. However, whether PPI use is associated with excess risk of death is unknown. We aimed to examine the association between PPI use and risk of all-cause mortality.

Design Longitudinal observational cohort study.

Setting US Department of Veterans Affairs.

Participants Primary cohort of new users of PPI or histamine H2 receptor antagonists (H2 blockers) (n=349 312); additional cohorts included PPI versus no PPI (n=3 288 092) and PPI versus no PPI and no H2 blockers (n=2 887 030).

Main outcome measures Risk of death.

Results Over a median follow-up of 5.71 years (IQR 5.11–6.37), PPI use was associated with increased risk of death compared with H2 blockers use (HR 1.25, CI 1.23 to 1.28). Risk of death associated with PPI use was higher in analyses adjusted for high-dimensional propensity score (HR 1.16, CI 1.13 to 1.18), in two-stage residual inclusion estimation (HR 1.21, CI 1.16 to 1.26) and in 1:1 time-dependent propensity score-matched cohort (HR 1.34, CI 1.29 to 1.39). The risk of death was increased when considering PPI use versus no PPI (HR 1.15, CI 1.14 to 1.15), and PPI use versus no PPI and no H2 blockers (HR 1.23, CI 1.22 to 1.24). Risk of death associated with PPI use was increased among participants without gastrointestinal conditions: PPI versus H2 blockers (HR 1.24, CI 1.21 to 1.27), PPI use versus no PPI (HR 1.19, CI 1.18 to 1.20) and PPI use versus no PPI and no H2 blockers (HR 1.22, CI 1.21 to 1.23). Among new PPI users, there was a graded association between the duration of exposure and the risk of death.

Conclusions The results suggest excess risk of death among PPI users; risk is also increased among those without gastrointestinal conditions and with prolonged duration of use. Limiting PPI use and duration to instances where it is medically indicated may be warranted.

  • CLINICAL PHARMACOLOGY
  • EPIDEMIOLOGY
  • Gastroduodenal disease
  • Health & safety
  • PUBLIC HEALTH
  • Adverse events

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • Contributors Research area and study design: YX, BB, TL, HX, YY and ZAA; data acquisition: YX and BB; data analysis and interpretation: YX, BB, TL, HX, YY and ZAA; statistical analysis: YX and BB; supervision and mentorship: ZAA. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. ZAA takes responsibility that this study has been reported honestly, accurately and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

  • Disclaimer The contents do not represent the views of the US Department of Veterans Affairs or the US Government.

  • Competing interests None declared.

  • Ethics approval This research project was reviewed and approved by the Institutional Review Board of the VA Saint Louis Health Care System.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data are available through the US Department of Veterans Affairs.