Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort studyBMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1580 (Published 30 May 2019) Cite this as: BMJ 2019;365:l1580
- Yan Xie, biostatistician12,
- Benjamin Bowe, biostatistician13,
- Yan Yan, professor14,
- Hong Xian, professor13,
- Tingting Li, associate professor15,
- Ziyad Al-Aly, director12567
- 1Clinical Epidemiology Center, Department of Veterans Affairs St Louis Health Care System, 915 North Grand Boulevard, St Louis, MO 63106, USA
- 2Veterans Research and Education Foundation of St Louis, St Louis, MO, USA
- 3Department of Biostatistics, College for Public Health and Social Justice, Saint Louis University, St Louis, MO, USA
- 4Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA
- 5Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
- 6Renal Section, Medicine Service, Department of Veterans Affairs Saint Louis Health Care System, St Louis, MO, USA
- 7Institute for Public Health, Washington University School of Medicine, St Louis, MO, USA
- Correspondence to: Z Al-Aly @zalaly on Twitter) (or
- Accepted 20 March 2019
Objective To estimate all cause mortality and cause specific mortality among patients taking proton pump inhibitors (PPIs).
Design Longitudinal observational cohort study.
Setting US Department of Veterans Affairs.
Participants New users of PPIs (n=157 625) or H2 blockers (n=56 842).
Main outcome measures All cause mortality and cause specific mortality associated with taking PPIs (values reported as number of attributable deaths per 1000 patients taking PPIs).
Results There were 45.20 excess deaths (95% confidence interval 28.20 to 61.40) per 1000 patients taking PPIs. Circulatory system diseases (number of attributable deaths per 1000 patients taking PPIs 17.47, 95% confidence interval 5.47 to 28.80), neoplasms (12.94, 1.24 to 24.28), infectious and parasitic diseases (4.20, 1.57 to 7.02), and genitourinary system diseases (6.25, 3.22 to 9.24) were associated with taking PPIs. There was a graded relation between cumulative duration of PPI exposure and the risk of all cause mortality and death due to circulatory system diseases, neoplasms, and genitourinary system diseases. Analyses of subcauses of death suggested that taking PPIs was associated with an excess mortality due to cardiovascular disease (15.48, 5.02 to 25.19) and chronic kidney disease (4.19, 1.56 to 6.58). Among patients without documented indication for acid suppression drugs (n=116 377), taking PPIs was associated with an excess mortality due to cardiovascular disease (22.91, 11.89 to 33.57), chronic kidney disease (4.74, 1.53 to 8.05), and upper gastrointestinal cancer (3.12, 0.91 to 5.44). Formal interaction analyses suggested that the risk of death due to these subcauses was not modified by a history of cardiovascular disease, chronic kidney disease, or upper gastrointestinal cancer. Taking PPIs was not associated with an excess burden of transportation related mortality and death due to peptic ulcer disease (as negative outcome controls).
Conclusions Taking PPIs is associated with a small excess of cause specific mortality including death due to cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer. The burden was also observed in patients without an indication for PPI use. Heightened vigilance in the use of PPI may be warranted.
Contributors: YX, BB, TL, HX, YY, and ZAA developed the research area and study design. YX and BB acquired the data. YX, BB, TL, HX, YY, and ZAA analyzed and interpreted the data. YX and BB performed the statistical analysis. ZAA supervised and mentored the team. 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. All authors had full access to the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. ZAA is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding: This research was funded by the United States Department of Veterans Affairs and the Institute for Public Health at Washington University in St Louis, MO, USA (ZAA). The funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: This research project (study# 1163689) was reviewed and approved by the Institutional Review Board of the Department of Veterans Affairs Saint Louis Health Care System.
Data sharing: All data are available through the United States Department of Veterans Affairs.
The lead author (ZAA) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a non-exclusive license (the corresponding author is a US Government employee) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in BMJ editions and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our license.”
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