Results from a longitudinal observational cohort study of US Veterans found that taking proton pump inhibitors (PPIs) may be associated with a small increase in cause-specific mortality, including death due to cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer, according to research results published in BMJ.

New users of acid suppression drugs identified in US Department of Veterans Affairs databases were selected between July 1, 2002 and June 30, 2004 and followed for up to 10 years; 157,625 were taking PPIs and 56,842 were taking histamine H2-receptor antagonists (H2 blockers). Study outcomes were specific causes of death based on the National Death Index. Sub-causes of death were then created based on evidence supporting a relationship between taking PPIs and adverse events that could cause mortality. These sub-causes included death due to cardiovascular disease, upper gastrointestinal cancer, Clostridium difficile infections, and chronic kidney disease.

In the overall cohort, the average age was 65 years (95.9% men; 87.4% white). Of new users of PPIs, rabeprazole 20 mg once per day, omeprazole 20 mg once per day, and rabeprazole 20 mg twice per day accounted for 58.78%, 21.66%, and 8.41% of all initial PPI prescriptions, respectively. Over a median follow-up of 10 years, there were 80,062 (37.33%) deaths. The most common causes of death were circulatory system diseases (12.45%), neoplasms (9.72%), and respiratory system diseases (4.80%). There were more deaths in patients taking PPIs than in patients taking H2 blockers (37.92% and 35.69%, respectively).

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To estimate the association between exposure to PPIs and causes of death, the researchers randomly assigned patients to new use of PPIs or H2 blockers for no more than 90 days. Per 1000 PPI users, there were 45.42 excess deaths, which were associated with circulatory system diseases (17.47 attributable deaths per 1000 PPI users), neoplasms (12.94), genitourinary system diseases (6.25), and infectious and parasitic diseases (4.20). Taking PPIs was not associated with increased mortality due to digestive system diseases.

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Sub-causes associated with an increased mortality included cardiovascular disease (15.48 attributable deaths per 1000 PPI users) and chronic kidney disease (4.19 attributable deaths per 1000 PPI users), but were not associated with upper gastrointestinal cancer (1.72) or Clostridium difficile infection (0.65).

“The evidence from all available studies suggests that long term PPI use is associated with serious adverse events, including an increased risk of all cause mortality, and our results specifically suggest an increased mortality due to cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer,” the investigators concluded.   


Xie Y, Bowe B, Yan Y, Xian H, Li T, Al-Aly Z. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study. BMJ. 2019;365: l1580.