Therapeutics Letter 126 considers serious harms with long-term proton pump inhibitor use in older adults. Conclusions: Observational studies have identified signals of serious harms from long-term PPI exposure, including an increased risk of death. Even large RCTs may not detect these, if exposure or follow-up are insufficiently long. The COMPASS trial findings are not inconsistent with contemporaneous findings from observational studies. Clinicians and patients can reverse the relentless expansion of long-term PPI exposure by reviewing indications and considering potential harms as well as benefits.

Long-term use of PPIs in older adults

We examined use of PPIs from 2008–2018 in people age 65 or older who filled a PPI prescription in BC during 2018. Of these older British Columbians, 64% had a cumulative exposure exceeding 2 years and 44% exceeded 5 years. Only 12% were dispensed PPIs for 90 days or less. In contrast, the recommended treatment duration is 4–8 weeks for common indications including reflux esophagitis, duodenal and gastric ulcers.

Starting in 2009, Health Canada and other regulators have reported a number of drug interactions and adverse events associated with PPIs, ranging from hypomagnesemia with hypocalcemia and hypokalemia to C. difficile associated diarrhea or fractures. Many professional associations and independent drug bulletins recommend reducing PPI exposure and provide tools for deprescribing^2,3,4,5 although they exclude conditions such as Barrett’s esophagus, severe esophagitis, or previous ulcer bleed. This Letter does not address those conditions.

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?

All-cause mortality - discordant or convergent findings?

Controversy persists over interpretation of evidence derived from randomised clinical trials (RCT) and epidemiological studies. Applying our usual hierarchy of clinical outcomes, we identified three recent studies (each using a different methodology) that provide evidence regarding all-cause mortality from PPI exposure of up to 10 years (Table 1).

Table 1

All-cause mortality estimates during long-term use of PPI (> 3 months)

The COMPASS (Cardiovascular Outcomes for People Using Anticoagulant Strategies) randomized controlled trial (RCT) assigned 17,598 people with stable atherosclerotic CV disease (but without an indication for PPI) to pantoprazole 40 mg/d vs. placebo.⁶ Participants also took rivaroxaban and/or ASA. COMPASS followed for a median of 3 years people whose mean exposure to pantoprazole was < 3 years. All-cause mortality was similar, although absolute numbers and hazard ratio favour placebo. Most non-fatal harm outcomes also numerically favour placebo. Pantoprazole increased enteric infections (mostly C. difficile) with an odds ratio of 1.33 (1.01–1.75), absolute risk increase 0.4%. The authors recognized that low event rates for some outcomes limited their ability “to exclude a modest risk increase” from pantoprazole.

In contrast, a US Veterans Affairs (VA) cohort study involving 214,467 people, and a systematic review and meta-analysis (SR/MA) involving 22,427, found increased all-cause mortality from long-term PPI therapy.^7,8

The US VA cohort study followed people for a median of 10 years. Median exposure to PPI of 4.6 years was longer than in the COMPASS RCT. The VA study included twelve times as many people as COMPASS, using national level administrative data collected from routine care transactions. Researchers used best available methodology, including an active comparator group defined by H₂ receptor antagonist prescriptions (H₂RAs), to minimize the risk of unidentified confounding.

The SR/MA of 3 observational studies that report mortality depends largely on a 2011 Danish retrospective study of 19,925 patients taking ASA after a first MI.⁹ Mortality was increased during 1 year follow-up in people taking PPIs; HR 2.38 (2.12–2.67). Use of H₂RA did not increase mortality.

Chronic conditions and increased susceptibility to infection: Serious harms associated with long-term PPI use differ from early intolerance or hypersensitivity. In clinical practice, they could easily be mistaken for early onset or deterioration of multi-factorial chronic conditions whose prevalence increases with age. Pharmacoepidemiologic studies using real-world observational data are a pragmatic way to detect such harms. We identified over 100 systematic reviews published during the last 5 years of specific harms associated with long-term PPI use.¹⁰ Table 2 shows relative risk estimates for some serious but less recognized harms, reproduced from the original publications.

Table 2

Recent estimates of association between PPI exposure and serious harms

Why use PPIs for so long? RCT evidence for PPIs supports treatment for 4–8 weeks for esophageal reflux, gastric and duodenal ulcers. RCTs, including the COMPASS effectiveness trial in people using antithrombotic drugs,¹⁵ have yet to prove that net benefits exceed harms during long-term use in older people.

Yet despite multiple signals of serious harm, 88% of people over age 65 taking PPIs in BC during 2018 had long-term exposure. Associations detected in observational studies are not proof of causation, but insisting on RCT evidence for fatal and serious adverse events from medication use contravenes modern standards in pharmacovigilance. The standard levels of evidence expected to confirm treatment benefits are not equally appropriate for protection of patients from potentially avoidable harms.

Conclusions

• Observational studies have identified signals of serious harms from long-term PPI exposure, including an increased risk of death.
• Even large RCTs may not detect these, if exposure or follow-up are insufficiently long. The COMPASS trial findings are not inconsistent with contemporaneous findings from observational studies.
• Clinicians and patients can reverse the relentless expansion of long-term PPI exposure by reviewing indications and considering potential harms as well as benefits.

References

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Choosing Wisely Canada. Toolkit: Bye-Bye, PPI. 2017. https:​//choosingwiselycanada​.org/perspective/ppi-toolkit/

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Xie Y, Bowe B, Yan Y, et al. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study. BMJ. 2019;365:l1580. DOI:10.1136/bmj.l1580 [PMC free article: PMC6538974] [PubMed: 31147311] [CrossRef]

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Charlot M, Grove EL, Hansen PR, et al. Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study. BMJ 2011;342:d2690. DOI:10.1136/bmj.d2690 [PMC free article: PMC3092520] [PubMed: 21562004] [CrossRef]

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Wan QY, Wu XT, Li N, et al. Long-term proton pump inhibitors use and risk of gastric cancer: a meta-analysis of 926 386 participants. Gut. 2019;68(4):762–764. DOI:10.1136/gutjnl-2018-316416 [PubMed: 29615489] [CrossRef]

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Wu B, Shang W, Li Y, et al. Association between proton pump inhibitors use and kidney diseases: A meta-analysis. International Journal of Clinical and Experimental Medicine. 2018;11(7):6465–6473. EMBASE: 20180549422

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Hussain S, Singh A, Habib A, Najmi AK. Proton pump inhibitors use and risk of chronic kidney disease: Evidence-based meta-analysis of observational studies. Clinical Epidemiology and Global Health. 2019;7(1):46–52. DOI:10.1016/j.cegh.2017.12.008 [CrossRef]

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Moayyedi P; Eikelboom JW; Bosch J et al. Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial. Gastroenterology 2019;157(2):403–412.e5. DOI:10.1053/j.gastro.2019.04.041 [PubMed: 31054846] [CrossRef]

The draft of this Therapeutics Letter was submitted for review to 130 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.

The Therapeutics Initiative is funded by the BC Ministry of Health through a grant to the University of BC. The Therapeutics Initiative provides evidence-based advice about drug therapy, and is not responsible for formulating or adjudicating provincial drug policies.