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.