Further Evidence to Monitor Long-term Proton Pump Inhibitor Use

Proton pump inhibitors (PPIs) are antiacid secretory agents that are first-line therapy for gastroesophageal reflux disease, peptic ulcer disease, and a wide range of other gastrointestinal disorders.¹ Proton pump inhibitors are among the most commonly dispensed drug classes in the United States; omeprazole alone was dispensed more than 70 million times in 2016,² and 1 in 10 of all patients with ambulatory care visits in the United States in 2009 had documented PPI use.³ In addition, over-the-counter formulations of PPIs have been available since 2003 for the short-term treatment of frequent heartburn. Although PPIs are effective and necessary long-term therapies for certain rare conditions, such as Zollinger-Ellison syndrome, most common indications for PPIs, such as gastroesophageal reflux disease, require only short-term use of the drugs and little evidence supports their long-term use.¹ However, unnecessary off-label long-term use of PPIs is prevalent, with up to 65% of patients receiving PPI therapy in the United States having no documented ongoing indication,⁴ raising concerns about inappropriate polypharmacy and its risks.¹ Although PPIs are considered safe overall, they have now been linked to numerous adverse events, including drug-drug interactions, hypomagnesemia, osteoporotic fractures, and serious infections.¹ The study by Vilcu and colleagues⁵ investigates an emerging concern of infectious complications associated with persistent PPI use: increased risk of acute gastroenteritis (AGE) during AGE epidemics.

The objective of the study by Vilcu and colleagues⁵ was to measure the association between continuous PPI therapy and the occurrence of AGE using a large French community-pharmacy drug dispensation database. The authors used a retrospective matched cohort design to estimate the association between PPI use and AGE incidence during an AGE epidemic period (the 5 weeks of peak AGE incidence in the winter of 2015 to 2016) among patients with at least 1 PPI prescription in the 100 days before and 100 days after the epidemic period. Incident AGE was defined using a drug dispensing algorithm previously found to correlate with an indicator for AGE in French general practitioner records.⁶

Vilcu and colleagues⁵ found a significant association between PPI use and AGE (relative risk, 1.81; 95% CI, 1.72-1.90), translating to a number needed to harm of 153 patients. Of note, the authors also found a significant association between AGE and histamine 2 receptor antagonists in a sensitivity analysis (adjusted relative risk, 2.08; 95% CI, 1.27-3.39). A significant association between PPI use and age was found, with older age groups (aged 45-64 years) at highest risk and younger age groups (aged 0-14 years and 15-44 years) at no significant increased risk. Vilcu et al⁵ concluded that continuous exposure to PPIs was associated with an increased risk of AGE during epidemic periods. Acute gastroenteritis was identified by the authors as another potential adverse effect of PPI therapy that possibly is more prevalent among older patients than younger ones. This risk is supported by the biological mechanism that PPIs may promote overgrowth of gut flora.⁵ These results align with those of previous studies^7,8 that identified associations between PPI use and incidence of specific enteric illnesses, including those caused by Clostridium difficile and norovirus (a prominent pathogen associated with AGE).⁵

Although Vilcu et al⁵ thoroughly address limitations of their study, including outcome ascertainment using drug dispensing data and confounding by indication, it is important to reiterate that the possibilities of residual confounding and protopathic bias remain, particularly because adjustment for comorbidities relied on drug dispensation information alone. In the study, as is common in many settings, patients receiving long-term PPI treatment were significantly sicker than non–PPI users. These patients may have a higher baseline risk of viral exposure and susceptibility to AGE due to excess frailty, compromised immunity, or increased contact with the health care system. The results are certainly intriguing and should be replicated.

Regardless of limitations, the study by Vilcu et al⁵ highlights a new potential risk of PPI therapy and offers important takeaway points related to the large number of higher-risk patients using PPIs and whether long-term therapy is indicated. Importantly, these results add to a growing body of literature supporting the importance of deprescribing of PPIs to reduce potential adverse effects. Deprescribing guidelines have been published to guide clinicians in stopping or dose-reducing inappropriate PPI therapy,¹ particularly among those with no present, identifiable indication for the drug. Discontinuation of inappropriate PPI therapy in older adults (aged ≥65 years) is also a component of the STOPP/START criteria⁹ and Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.¹⁰ In addition to medical record reviews to discontinue inappropriately prescribed PPI therapy, clinicians should also ask patients about over-the-counter medication use to comprehensively screen for PPI deprescribing opportunities. Indications for long-term PPI therapy in ambulatory patients should be limited to prevention of nonsteroidal anti-inflammatory drug–induced ulcers, severe esophagitis, Barrett esophagus, idiopathic chronic ulcer, refractory gastroesophageal reflux disease, pathologic hypersecretory conditions (eg, Zollinger-Ellison syndrome), and certain patients with a history of gastrointestinal ulcer with bleeding.¹ Potential candidates for deprescribing include patients with a history of Helicobacter pylori infection, peptic ulcer disease, heartburn, dyspepsia, or gastroesophageal reflux disease but no present indication for antisecretory treatment.¹ In addition, an overall evaluation of the need for any acid-reducing therapy should be considered first, rather than simply switching from PPIs to histamine 2 receptor antagonist therapy, given that both PPIs and histamine 2 receptor antagonists were associated with AGE incidence in the study by Vilcu et al.⁵

The study by Vilcu et al⁵ flags yet another potential risk of therapy with what was previously thought to be a generally safe drug class. Asking patients about all medication use, including over-the-counter drugs, and understanding why a patient is using a PPI are imperative to identifying deprescribing needs and reducing adverse drug effects. For patients with a documented indication for PPI use, clinicians should ensure that the expected benefits are balanced against the risks of PPI therapy and that the lowest effective dose be used for the shortest recommended duration.

Published: November 27, 2019. doi:10.1001/jamanetworkopen.2019.16184

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Hayes KN et al. JAMA Network Open.

Corresponding Author: Mina Tadrous, PharmD, MS, PhD, Women’s College Hospital, 76 Grenville St, Toronto, ON M5V 3C9, Canada (mina.tadrous@wchospital.ca).

Conflict of Interest Disclosures: Dr Nakhla reported receiving personal fees from Pfizer outside the submitted work. No other disclosures were reported.