Introduction
Prescription proton pump inhibitors (PPIs) are primarily approved for short‐term use (2 to 8 weeks) for peptic ulcer disease (PUD), reflux esophagitis and non-ulcer dyspepsia 1. Longer-term indications include gastric bleeding, severe esophagitis or Barrett’s esophagus or to prevent gastric damage associated with adverse effects of other drugs. However, these long-term indications only account for a small proportion of long-term PPI use in Canada, which exceeds 10% of the adult population 2,3.
The short-term benefits of PPIs as a drug class are not disputed4,5. However, the belief that the positive net benefit to harm ratio with short-term treatment extends to long-term use (greater than 12 weeks) has been challenged by post-market analyses6-9.
Health Canada 10 has issued warnings for a number of adverse events and drug interactions that were not recognized when the first PPIs were approved 30 years ago: hypomagnesemia accompanied by hypocalcemia and hypokalemia (2011), clostridium difficileassociated diarrhea (2012), bone fractures (2013), subacute cutaneous lupus erythematosus (2017) as well as new drug interactions with clopidogrel (2009) and methotrexate (2012). There are US Food and Drug Administration warnings for PPI use and risk of increased risk of bone fractures, clostridium difficult infection (CDI ) and profound hypomagnesemia.
A number of professional associations and independent drug bulletins recommend reducing PPI exposure and provide tools for de-prescribing11,12. Encouraging restraint has yet to achieve a measurable impact on long-term PPI prescribing for the common indications. Is the evidence of harms sufficient that we should intensify efforts to constrain new prescriptions and to deprescribe for long-term users?
Recently in our 2016 systematic review, we reported on the comparative effectiveness of PPIs, benefits and harms, as well as evidence for considering deprescribing 4,5. In many clinical settings, we do not know whether the benefits of long-term PPI use outweigh the harms. Harms were underreported in RCTs that directly compared different PPIs. Mortality, SAE, and withdrawal due to adverse events were not reported 4,5. Longer duration, head-to-head comparative RCTs specifically designed to monitor adverse effects have not been conducted.
Recent evidence from a clinical trial 13 has raised doubts on a growing consensus from observational studies and systematic reviews of observational studies that PPI exposure is associated with increased risk of death; the risk increases with increased exposure14-16. Therefore, the aim of this review is to summarize and critically examine evidence from systematic reviews and primary studies reporting all-cause mortality.