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Patients in both primary and secondary cohorts were followed until 30 September 2013 or death.The study was approved by the Institutional Review Board of the VA Saint Louis Health Care System, Saint Louis, Missouri.

T0 for secondary cohorts was defined as 1 October 2006.We hypothesised that owing to the consistently observed associations between PPI use and risk of adverse health outcomes, PPI use is associated with excess risk of death, and that the risk of death would be more pronounced with increased duration of use.We therefore used the Department of Veterans Affairs national databases to build a longitudinal cohort of incident users of acid suppression therapy, including PPI and histamine H2 receptor antagonists (H2 blockers), to examine the association between PPI use and risk of all-cause mortality and to determine whether risk of death is increased with prolonged duration of use.The VA Vital Status and Beneficiary Identification Records Locator Subsystem files provided demographic characteristics and death. Once cohort participants received PPI prescription, they were considered with the effect of PPI until the end of follow-up.Medications that contain esomeprazole, lansoprazole, omeprazole, pantoprazole or rabeprazole were counted as PPI.All covariates except for age, race and gender covariates values were treated as time-varying covariates where they were additionally assessed until the date of the first PPI prescription in those patients who did not have PPI prescription at T0.

Any comorbidity occurring during the assessment period was considered present during the remaining follow-up.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).Medications including ranitidine, cimetidine and famotidine were counted as H2 blockers.Covariates included age, race, gender, e GFR, number of outpatient serum creatinine measurements, number of hospitalisations, diabetes mellitus, hypertension, cardiovascular disease, peripheral artery disease, cerebrovascular disease, chronic lung disease, cancer, hepatitis C, HIV, dementia and diseases associated with acid suppression therapy use such as gastro-oesophageal reflux disease (GERD), upper gastrointestinal (GI) tract bleeding, ulcer disease, infection, Barrett's oesophagus, achalasia, stricture and oesophageal adenocarcinoma.25–28 e GFR was calculated using the abbreviated four-variable CKD epidemiology collaboration equation based on age, sex, race and outpatient serum creatinine.29 Race/ethnicity was categorised as white, black or other (Latino, Asian, Native American or other racial/ethnic minority groups).Objective Proton pump inhibitors (PPIs) are widely used, and their use is associated with increased risk of adverse events.

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