PPIs are the leading evidence-based therapy for acid-related diseases due to their efficacy and safety profile, and the reduction in costs due to availability of generic formulations.2
These factors have contributed to overprescribing of PPIs, with up to 60% of primary care physicians making no attempt to reduce patients’ doses over time, and almost 50% of patients receiving long-term PPI therapy having no clear indication for its continuation.3
Despite their reputation for tolerability, the number of publications dealing with PPI-related adverse outcomes from long-term use has steadily increased in proportion to their widespread uptake.4-6 Several studies have examined the link between PPI use and increased risk of mortality; some found an association;7-9 others did not.10
This article adds to that body of literature. In this study the authors hypothesised that, owing to the consistently observed associations between PPI use and risk of adverse health outcomes, PPI use is associated with excess risk of death.1
Although they state that the biological mechanism underpinning the association of PPI use and risk of death is unclear, the claim is made that the heightened risk of death can be plausibly explained by clinical changes (kidney disease, dementia, hypomagnesaemia, pneumonia, osteoporotic fracture, etc) associated with adverse events from PPI use.
As with most studies published on this subject, this study used an observational design.
Unlike randomised controlled trials, observational studies can only provide evidence for the presence or absence of an association, as opposed to establishing a causal link between PPI use and adverse outcomes (such as mortality), although many RCTs suggest a causal link without being able to suggest the mechanism for this.
Residual bias is a problem in observational studies because even with complex statistical methods it is difficult to adjust for all confounding factors, some of which may be unknown and hence unmeasurable.11 Although the findings of the study showed a very precise association, reflected in the low p values and narrow confidence intervals, this is not an indication of causality.12
Moreover, the effect sizes presented here only provide evidence of a weak association (all hazard ratios < 2). When effect sizes are small (relative risk / odds ratio / hazard ratio < 2), it is not possible to determine whether the association is valid or represents the result of residual bias.13
Effect sizes for PPI use and some reported adverse effects (eg, dementia, chronic kidney disease, any fracture, or community-acquired pneumonia) are consistently reported as being ≤ 2.0,4,14,15 translating into small increases in absolute excess risk.16
Thus, although the findings were statistically significant, they are unlikely to be large enough to be clinically relevant, as the background risk is small.
Nonetheless, if true causality exists, even small effect sizes can represent a meaningful risk for common interventions and conditions, particularly given the widespread extent of use of PPIs.17
The link between PPI use and acute interstitial nephritis (AIN) is a good example, particularly as the authors of this paper previously published on this topic, based on findings from the same database.15 In that study, more than half of the cases of chronic kidney damage and end-stage renal disease associated with PPI use occurred in people without acute kidney problems.
Numerous case reports and case series have been published describing the association between PPIs and AIN, many of which were biopsy-proven.18-20 In fact, PPIs are now considered to be one of the most common causes of drug-induced AIN worldwide,21 although the precise mechanism is unknown.
The diagnostic utility of symptoms, signs or laboratory tests of PPI-induced AIN is poor, increasing the likelihood that PPI-induced AIN in the general population may be missed.
The time interval from starting PPI therapy to the development of clinical AIN is quite variable.22 While clinical presentation is on average 9.9 weeks, symptoms appear anywhere between 1 week and 9 months after initial exposure to the PPI.23 This differs from the classic 10–14-day timeframe seen with many drugs.23
Some patients with AIN have developed varying degrees of chronic kidney disease (CKD).24-26 The risk of CKD is increased in PPI users compared with non-PPI users, and the prevalence is related to the dose and duration of administration.14,15
The best available evidence on long-term safety of PPIs (in terms of the hierarchy of evidence)27 derives from the Safety of Omeprazole in Peptic Reflux Esophagitis: A Nordic Open Study (SOPRAN)28 and Long-Term Usage of Esomeprazole vs Surgery for Treatment of Chronic GERD (LOTUS)29 randomised controlled trials.
Safety data were collected from patients during the 12-year period of the SOPRAN study (n = 298) and the 5-year period of the LOTUS study (n = 514). Across both studies, serious adverse events were reported at a similar frequency in the PPI and comparator group.
Laboratory results, including routine haematology and tests for liver enzymes, electrolytes, vitamin D, vitamin B12, folate, and homocysteine showed no clinically relevant changes over time.30
Only patients responsive to initial PPI therapy were included in these studies. Patients with significant comorbidities and those considered likely to be poorly compliant were excluded.