Do proton pump inhibitors increase mortality? A systematic review and
in-depth analysis of the evidence
Abstract
Aims: 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. Methods: We searched MEDLINE, Embase
and Cochrane Central for evidence from systematic reviews (SR) 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). Data was
synthesized, analysed, critically examined and interpreted herein.
Results: From 1304 articles, one systematic review (SR) was identified
that reported on all-cause mortality. The SR pooled 3 observational
studies with data to 1 year: odds ratio, 95% confidence interval (CI)
1.53-1.84. A randomized controlled trial (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; HR 1.17, 95% CI (1.10-1.24), (NNH) 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
10-year period. Conclusions: 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 varied study designs.
Careful appraisal of the totality of available evidence leads to the
conclusion that long-term PPI utilization increases mortality