Do proton pump inhibitors increase mortality? A systematic review and in‐depth analysis of the evidence

Proton pump inhibitors (PPIs) were primarily approved for short‐term use (2 to 8 weeks). However, PPI use continues to expand. Widely believed to be safe, we reviewed emerging evidence on increased mortality with PPI long‐term use. Our 2016 systematic PPI drug class review found that mortality was not reported as an outcome in randomized controlled trials (RCTs) that directly compared different PPIs. We sought more recent and comprehensive data on PPI harm outcomes from research syntheses as a follow‐on. A search was conducted from January 2014 to January 2020. We searched MEDLINE, EMBASE, and Cochrane Central for evidence from systematic reviews (SRs) and primary studies reporting all‐cause mortality in adults treated with a PPI for any indication (duration >12 weeks) compared to patients without PPI treatment (no use, placebo, or H2RA use). Two independent investigators assessed study eligibility, synthesized evidence, and assessed the quality of the included studies. Data on all‐cause mortality were sought, analyzed, critically examined, and interpreted herein. From 1304 articles, one SR was identified that reported on all‐cause mortality. The SRs pooled three observational studies with data to 1 year: odds ratio, 95% confidence interval (CI) 1.53‐1.84. A RCT, the COMPASS (Cardiovascular Outcomes for People Using Anticoagulant Strategies) RCT with data to 3 years: hazard ratio (HR) 1.03, 95% CI 0.92‐1.15. The US Veterans Affairs cohort study using a large national dataset with data to 10 years found a HR of 1.17, 95% CI (1.10‐1.24) and (NNH) of 22. The most common causes of death were from cardiovascular and chronic kidney diseases, with an excess death of 15 and 4 per 1000 patients, respectively, over the 10‐year period. Harms arising from real‐world medication use are best evaluated using a pharmacovigilance “convergence of proof” approach using data from a variety of sources and various study designs. Given that most PPI indications for use recommended a treatment duration of less than 12 weeks, it seems clear that PPIs were significantly overused in older patients. The median exposure time to PPI ranged from 1 to 4.6 years. Signals of serious harms including increased mortality with long‐term PPI use are reported in observational studies. The COMPASS trial findings are not inconsistent with contemporaneous findings from observational studies. The COMPASS RCT was unlikely to detect an increase in mortality given the trial was not powered to detect th